rs11971167

chr7-117642528-G-Achr7-117642528-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1 PM5 BP4_Strong BS2

The NM_000492.4(CFTR):c.3808G>A(p.Asp1270Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000786 in 1,613,596 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1270Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:9 B:5
• Conservation: PhyloP100: 9.43

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117642529-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1706020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.016417444).
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3808G>A	p.Asp1270Asn	missense_variant	23/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3808G>A	p.Asp1270Asn	missense_variant	23/27	1	NM_000492.4	P2
	ENST00000456270.1	n.65+4823C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152118 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00479

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 250960 Hom.: 2 AF XY: 0.000811 AC XY: 110 AN XY: 135610

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000435 AC: 635 AN: 1461360 Hom.: 4 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 726956

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152236 Hom.: 6 Cov.: 33 AF XY: 0.00387 AC XY: 288 AN XY: 74438

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000705 Hom.: 1

Bravo AF: 0.00555

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00146 AC: 177

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2023	The p.D1270N variant (also known as c.3808G>A) is located in coding exon 23 of the CFTR gene in the NDB2 domain. This alteration results from a G to A substitution at nucleotide position 3808. The aspartic acid at codon 1270 is replaced by asparagine, an amino acid with some highly similar properties. This variant is typically found as part of the complex allele p.[R74W; V201M; D1270N] (de Prada Merino A et al. J. Cyst. Fibros. 2010; 9(6):447-9). This complex allele has been identified in the homozygous state and in trans with a pathogenic mutation in CFTR in individuals with CBAVD (Steiner B et al. Hum. Mutat. 2011; 32(8):912-20). This alteration has also been identified in individuals with pancreatitis (Masson E et al. PLoS One, 2013 Aug;8:e73522). One functional study found that this alteration resulted in normal protein processing, but it had a lower rate of cAMP-responsive anion conductance than the wild-type allele, similar to that of the p.R117H mutation (Fanen P et al. FEBS Lett. 1999;452(3):371-374). However, this alteration has also been described in trans with deleterious mutations in CFTR in healthy individuals, though CBAVD was not ruled out (Claustres M et al. BMC Med Genet. 2004;5:19; Brugnon F et al. Fertil Steril. 2008;90(5):2004.e23-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of evidence, this variant is not likely to cause classic CF; however, its role in CFTR-related conditions is unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 20, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 11, 2020	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	The D1270N variant in the CFTR gene has been reported previously in trans with the common delta F508 pathogenic variant in an individual with normal sweat chloride levels, a normal chest roentgenogram but who had CAVD (Anguiano et al., 1992). Expression studies in HeLa and FRT cells showed that D1270N transfected cells displayed decreased chloride transport activity compared to wild type cells (Fanen et al., 1999; Van Goor et al., 2014). However, D1270N has also been identified unaffected individuals who were compound heterozygous for D1270N and a definitively pathogenic variant (Sugarman et al., 2014). The D1270N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D1270N as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	- -

Hereditary pancreatitis Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 15, 2018	The CFTR c.3808G>A, p.Asp1270Asn variant (rs11971167) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (CBAVD), in trans with p.Phe508del (Anguiano 1992, Oates 1993), but is more commonly found in a complex allele (with p.Arg74Trp and p.Val201Met) in patients with CBAVD and pancreatitis (Bareil 2007, Casals 1995, Masson 2013, Steiner 2011). In individuals where the p.Asp1270Asn alone was reported in trans with p.Phe508del, they had normal or slightly elevated sweat chloride levels (Anguiano 1992, Padoa 1999). Functional characterization of the p.Asp1270Asn variant indicates reduced overall mRNA and protein expression (van Goor 2014), reduced chloride conductance (Sosnay 2013, van Goor 2014) and altered response patterns (Fanen 1999). However, protein maturation and glycosylation is comparable to wildtype (Fanen 1999, Sosnay 2013, van Goor 2014). This variant is found in the general population with an overall allele frequency of 0.1% (315/276666 alleles, including 3 homozygotes) in the Genome Aggregation Database. The aspartate at residue 1270 is highly conserved, and computational algorithms ( PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as very mildly pathogenic. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	Variant summary: CFTR c.3808G>A (p.Asp1270Asn) results in a conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domain of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 170702 control chromosomes (gnomAD v3 database and publications), including 6 homozygotes. This frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis phenotype (0.013). However, this variant is frequently reported in complex (i.e. in cis) with either the c.220C>T (p.Arg74Trp) and/or c.601G>A (p.Val201Met). The first two variants (i.e. R74W and D1270N) were individually found in control databases at very similar frequencies and allele counts (with the same number of homozygotes) in the African subpopulation. Therefore, although it is not possible to confirm that these variants occurred in the same individuals, it is very likely that the majority of the gnomAD (v3) population carried the [R74W;D1270N] complex allele. The variant has been reported in numerous patients with CF, CBAVD, lung cancer, idiopathic chronic pancreatitis, and recurrent respiratory infections without strong evidence for causality (e.g. Alonso_2007, Bombieri_1998, Masson_2013, Mercier_1995, Steiner_2011, Verlingue_1993) and it was determined to co-occur frequently on the same allele with R74W. The variant's complex forms, p.[R74W;D1270N] and p.[R74W;V201M;D1270N], are found in patients with CBAVD phenotype (e.g. Claustres_2000, Clausters_2004, Ratbi_2007, Steiner_2011, Minso_2020, UMD database). The variant in its complex form did not cause CF in females when found in a compound heterozygous state with a disease-causing mutation (Claustres_2000, Verlingue_1993) and similarly, did not cause disease when reported as the single variant in trans with pathogenic mutations in male individuals (Terlizzi_2017). Functional studies showed that this variant was associated with mildly reduced cAMP-activated chloride conductance activity and a slight reduction in the synthesis of mature CFTR protein (Fanen_1999, Terlizzi_2017, Van Goor_2013). One publication states that clinical and functional data "indicate that such mutations are not enough to cause disease" when discussing the variant as a single allele or a complex allele with R74W (Terlizzi_2017). Multiple ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), likely benign/benign (n=5), pathogenic/likely pathogenic with varying clinical consequences (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 18, 2018	The p.Asp1270Asn variant in CFTR has been reported in isolation or as part of th e p.[Arg74Trp;Asp1270Asn] complex allele in several individuals with CFTR-relate d conditions (Aguiano 1992, Casals 1995, Fanen 1999, Padoa 1999, Ravnik-Glavac 2 000, Luzardo 2002, Girodon 2002, Masson 2013, Sosnay 2013, Terlizzi 2017, Behar 2017). However, it has also been identified in isolation in trans with known pat hogenic CFTR variants in 2 unaffected adult male individuals and as part of the p.[Arg74Trp;Asp1270Asn] allele in trans with a known pathogenic variant in 1 una ffected child (Terlizzi 2017). It has also been identified with the p.Val201Met allele as part of the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele in severa l individuals with CFTR-related conditions who carried additional pathogenic var iants in CFTR (Claustres 20004, Brugnon 2008, de Prada Merino 2010, Steiner 2011 , Masson 2013, Terlizzi 2017). However, the p.[Arg74Trp;Val201Met;Asp1270Asn] al lele has also been identified in trans with the p.Phe508del in twin boys who are reportedly unaffected, although the paper did not specify if they were examined for CBAVD (Brugnon 2008). In addition, the p.Asp1270Asn variant has been identi fied in 1.3% (315/24024) of African chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In sum mary, the p.Asp1270Asn variant in isolation or as part of the p.[Arg74Trp;Asp127 0Asn] complex allele is classified as likely benign based on the high allele fre quency and the presence of this variant in trans with known pathogenic variants in unaffected individuals, though the clinical significance of the p.[Arg74Trp;V al201Met;Asp1270Asn] complex allele is uncertain. ACMG/AMP Criteria applied: BS1 , BP2. -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

CFTR-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The CFTR c.3808G>A variant is predicted to result in the amino acid substitution p.Asp1270Asn. This variant has been reported in patients with congenital bilateral absence of the vas deferens (Anguiano et al. 1992. PubMed ID: 1545465; Oates et al. 1993. PubMed ID: 8343799; Padoa et al. 1999. PubMed ID: 9950364; Chamayou et al. 2020. PubMed ID: 32357917), but has also been observed in the homozygous or compound heterozygous state in asymptomatic individuals (Terlizzi et al. 2017. PubMed ID: 27738188; Chamayou et al. 2020. PubMed ID: 32357917). The p.Asp1270Asn variant resulted in minimal disruption to CFTR processing in HeLa and FRT cells, suggesting normal CFTR maturation (Fanen et al. 1999. PubMed ID: 10386624; Sosnay et al 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). In FRT cells, the p.Asp1270Asn variant retained nearly half of wild-type CFTR chloride channel transport function, which was restored to wild-type levels with ivacaftor, suggesting a mild defect in channel conductance (Sosnay et al 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). Consistent with this, in HeLa cells, the p.Asp1270Asn variant impaired cAMP-responsive anion conductance of CFTR (Fanen et al. 1999. PubMed ID: 10386624). The p.Asp1270Asn variant is documented in 57 patients in the CFTR2 database with an average sweat chloride concentration of 57 mEq/L, compared to an average of 96 mEq/L for all patients in CFTR2 with two CF-causing variants (cftr2.org). This variant is reported in up to ~1.4% of alleles in individuals of African descent in gnomAD, including three homozygous individuals of unknown phenotype. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7164). In summary, due to conflicting genetic and functional evidence, the clinical significance of the p.Asp1270Asn variant is uncertain. Of note, the p.Arg74Trp and p.Asp1270Asn variants have been reported in linkage (on the same allele) and are collectively referred to as p.[Arg74Trp;Asp1270Asn]. Variant phasing information in gnomAD indicates that the p.Arg74Trp and p.Asp1270Asn variants likely occur in cis within the African, Latino/Admixed American and European (non-Finnish) subpopulations, but may rarely occur independently of each other. Consistent with this, one study observed that 94% of individuals carrying the p.Asp1270Asn variant also carried the p.Arg74Trp variant (Sugarman et al. 2004. PubMed ID: 15371903). The p.[Arg74Trp; Asp1270Asn] complex allele has been reported in compound heterozygous individuals with CBAVD and obstructive bronchitis (Claustres et al. 2004. PubMed ID: 15287992; Terlizzi et al. 2017. PubMed ID: 27738188; Chamayou et al. 2020. PubMed ID: 32357917), but has also been observed in the compound heterozygous state in asymptomatic individuals (Verlingue et al. 1993. PubMed ID: 7513889; Claustres et al. 2004. PubMed ID: 15287992; Terlizzi et al. 2017. PubMed ID: 27738188). In HeLa cells, the p.[Arg74Trp; Asp1270Asn] variant did not affect CFTR processing but did result in impaired cAMP-responsive anion conductance (Fanen et al. 1999. PubMed ID: 10386624). The authors suggest that both variants together may lead to a synergistic effect to further impair CFTR function than either variant in isolation (Fanen et al. 1999. PubMed ID: 10386624; Claustres et al. 2004. PubMed ID: 15287992). In addition, Sosnay et al. in a comprehensive study of CFTR variants classified these variants as “indeterminate” (Sosnay et al 2013. PubMed ID: 23974870). In ClinVar, the complex allele p.[Arg74Trp; Asp1270Asn] is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/977735). In summary, due to the conflicting genetic and functional evidence, the clinical significance of the complex p.[R74W; D1270N] variant is also uncertain. -

CFTR-related disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.059	T;T;.
Polyphen		1.0	D;.;.
Vest4		0.84
MVP		1.0
MPC		0.010
ClinPred		0.027	T
GERP RS		5.2
Varity_R		0.74
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11971167; hg19: chr7-117282582;