rs397508569
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000492.4(CFTR):āc.3461A>Gā(p.Asp1154Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,666 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1154N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3461A>G | p.Asp1154Gly | missense_variant | 21/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3461A>G | p.Asp1154Gly | missense_variant | 21/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.177+1523T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250930Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135632
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1455666Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2AN XY: 724528
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2023 | Variant summary: CFTR c.3461A>G (p.Asp1154Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250930 control chromosomes. c.3461A>G has been reported in the literature as a non-informative genotype (second allele not specified) in individuals affected with CBAVD/CAVD and Cystic Fibrosis (Claustres_2000, Green_2010, Yang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis/CFTR-related disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired chloride channel activity (Vankeerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 20932301, 9804160, 26277102). CFTR-France database has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Cystic fibrosis Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at