rs397508670

Positions:

• chr7-117664815-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000492.4(CFTR):​c.4091C>T​(p.Ala1364Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1364A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 O:1
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 14 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.4091C>T	p.Ala1364Val	missense_variant	25/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4091C>T	p.Ala1364Val	missense_variant	25/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251250 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461730 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74414

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:5 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 05, 2022	The p.A1364V variant (also known as c.4091C>T), located in coding exon 25 of the CFTR gene, results from a C to T substitution at nucleotide position 4091. The alanine at codon 1364 is replaced by valine, an amino acid with similar properties. This variant was reported in conjunction with p.F508del in an individual with congenital absence of the vas deferens (CBAVD) (de Meeus A et al. Hum. Mutat., 1998;11:480). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1364 of the CFTR protein (p.Ala1364Val). This variant is present in population databases (rs397508670, gnomAD 0.02%). This missense change has been observed in individuals with congenital bilateral absence of vas deferens and/or pancreatitis (PMID: 10200050, 17003641, 21520337). ClinVar contains an entry for this variant (Variation ID: 53885). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 13, 2023	The CFTR c.4091C>T; p.Ala1364Val variant (rs397508670) is reported in the literature in two individuals affected with CBAVD co-occurring with another pathogenic CFTR variant (de Meeus 1998, Luo 2021). In addition, this variant had been reported as heterozygous in an individual with pancreatitis (Keiles 2006). This variant is also reported in ClinVar (Variation ID: 53885). This variant is found in the general population with an allele frequency of 0.004% (9/251250 alleles) in the Genome Aggregation Database. The alanine at codon 1364 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.754). However, given the lack of clinical and functional data, the significance of the p.Ala1364Val variant is uncertain at this time. References: de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. PMID: 10200050. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Luo S et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 20, 2022	PP3, PM2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 18, 2023

Variant summary: CFTR c.4091C>T (p.Ala1364Val) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 255050 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (3.9e-05 vs 0.013), allowing no conclusion about variant significance. c.4091C>T has been reported in the literature as a compound heterozygous genotype with p.F508del in at-least one individual affected with CAVD (example, deMeeus_1997) or in the absense of a second variant (example, Luo_2021). It has also been reported in heterozygote inviduals affected with pancreatitis (example, Keiles_2006) or with a CF-like disorder associated with AGR2 mutations, in which the patient had a negative sweat chloride test (Bertolli-Avella_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 20059485, 21520337, 22483971, 11504857, 10200050, 25735457, 26277102, 25880441, 32777524, 34740355, 34952832, 35913788). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=6). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Dec 30, 2017

- -

CFTR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2023

The CFTR c.4091C>T variant is predicted to result in the amino acid substitution p.Ala1364Val. This variant is predicted to generate a cryptic splicing donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has been reported in the heterozygous state in multiple individuals with congenital absence of vas deferens, and in one individual was reported along with a p.Phe508del variant (de Meeus et al. 1997. PubMed ID: 10200050; Supporting Table S5, Steiner et al. 2011. PubMed ID: 21520337; Table 1, Luo et al. 2020. PubMed ID: 32777524). This variant has also been reported in the heterozygous state in an individual with pancreatitis (Table 2, Keiles et al. 2006. PubMed ID: 17003641). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117304869-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.90		Gain of methylation at K1365 (P = 0.0377);.;.;
MVP		1.0
MPC		0.011
ClinPred		0.80	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397508670; hg19: chr7-117304869; COSMIC: COSV50040501;