chr7-117642472-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.3752G>A(p.Ser1251Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,738 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 Pathogenic,drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1251T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3752G>A | p.Ser1251Asn | missense_variant | 23/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3752G>A | p.Ser1251Asn | missense_variant | 23/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.65+4879C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251074Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135690
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461410Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 726996
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74486
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 07, 2019 | NM_000492.3(CFTR):c.3752G>A(S1251N) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3752G>A(S1251N) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2022 | The p.S1251N pathogenic mutation (also known as c.3752G>A and 3884G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3752. The serine at codon 1251 is replaced by asparagine. This mutation was first reported in two individuals with pancreatic insufficiency (PI), severe pulmonary disease, and gastrointestinal disease; both individuals carried the p.F508C alteration in cis and the p.F508del mutation in trans (Kälin N, et al. Hum Mutat. 1992; 1(3):204-10). This mutation is associated with elevated sweat chloride levels, lung disease, and PI; in addition, a functional study found this mutation resulted in significantly decreased rates of chloride conductance (Sosnay PR, et al. Nat Genet. 2013; 45(10):1160-7, Supplementary Table). Based on the supporting evidence, p.S1251N is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 02, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2023 | This missense change has been observed in individuals with cystic fibrosis (PMID: 1284535, 17481968, 23974870, 26989879). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 22293084). 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. ClinVar contains an entry for this variant (Variation ID: 7217). This variant is present in population databases (rs74503330, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1251 of the CFTR protein (p.Ser1251Asn). - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 04, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
CFTR-related disorder Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 02, 2019 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2017 | Variant summary: The CFTR c.3752G>A (p.Ser1251Asn) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/240702 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous CF patients worldwide and functional studies showed variant with defective channel opening and chloride transport (<10% normal CFTR). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 13, 2023 | - - |
ivacaftor response - Efficacy Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at