rs397508468
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000492.4(CFTR):c.2977G>T(p.Asp993Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,878 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).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2977G>T | p.Asp993Tyr | missense_variant | Exon 18 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.06e-7 AC: 1AN: 1415878Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1AN XY: 707510
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:1Other:1
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The p.D993Y variant (also known as c.2977G>T), located in coding exon 18 of the CFTR gene, results from a G to T substitution at nucleotide position 2977. The aspartic acid at codon 993 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was reportedly detected in trans with deltaF508 in the CFTR gene in two patients with severe lung disease, a positive sweat test, who were pancreatic insufficient (Claustres et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids; 1995 & 1997). This variant was also reported in a Chinese male with CBAVD; a second alteration was not identified (Li H et al. J Cyst Fibros. 2012;11(4):316-23). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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not specified Uncertain:1
Variant summary: CFTR c.2977G>T (p.Asp993Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251120 control chromosomes (gnomAD). c.2977G>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Claustres_2000, des Georges_2004, Dugueperoux_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at