rs397508621

chr7-117642592-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000492.4(CFTR):c.3872A>G(p.Gln1291Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,460,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. Q1291H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.00

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117642593-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7152.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-117642592-A-G is Pathogenic according to our data. Variant chr7-117642592-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53827.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2}. Variant chr7-117642592-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3872A>G	p.Gln1291Arg	missense_variant, splice_region_variant	23/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3872A>G	p.Gln1291Arg	missense_variant, splice_region_variant	23/27	1	NM_000492.4	P2
	ENST00000456270.1	n.65+4759T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250580 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460994 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: CFTR c.3872A>G (p.Gln1291Arg) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these splicing predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250580 control chromosomes (gnomAD). c.3872A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (e.g. Doerk_1994, Lucarelli_2015). These data indicate that the variant is very likely to be associated with disease. Functional assays using CFTR deficient Bronchial Epithelial cells showed the variant had 62.3% residual activity, with the authors concluding the variant had varying clinical consequences (Rareigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 7525450, 25910067, 29805046). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2019	The p.Q1291R variant (also known as c.3872A>G), located in coding exon 23 of the CFTR gene, results from an A to G substitution at nucleotide position 3872. The glutamine at codon 1291 is replaced by arginine, an amino acid with highly similar properties. This variant was identified in conjunction with p.F508del in an individual with pancreatic insufficient cystic fibrosis (CF) (Dörk T et al. Hum. Genet., 1994 Nov;94:533-42). In a cohort of individuals with CF and CFTR-related disorders, this variant was detected in the homozygous state; however, clinical information was not provided (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403). This variant was also detected in conjunction with p.F508del in an individual with abnormal newborn screening, equivocal sweat chloride results, and an abnormal nasal potential difference (Sermet-Gaudelus I et al. Thorax, 2010 Jun;65:539-44). It was the only variant identified in an individual with congenital bilateral absence of the vas deferens (Bienvenu T et al. Hum. Genet., 1995 Jun;95:698-702). Analysis of a rectal biopsy from an individual with this variant demonstrated aberrant splicing from the Q1291R allele due to use of a cryptic splice site and resulting in the inclusion of 29 base pairs and predicted to create a premature stop codon (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7). Functional analysis of this variant in CFBE cells demonstrated 62% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). The p.Q1291R alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). 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. -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jul 24, 2015

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 02, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.6	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.012	D;D;.
Polyphen		0.049	B;.;.
Vest4		0.79
MutPred		0.98		Gain of MoRF binding (P = 0.0148);.;.;
MVP		0.99
MPC		0.0052
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508621; hg19: chr7-117282646;