chr7-117642528-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000492.4(CFTR):c.3808G>T(p.Asp1270Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,362 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 drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1270N) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3808G>T | p.Asp1270Tyr | missense_variant | Exon 23 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461362Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726956
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:1
The p.D1270Y variant (also known as c.3808G>T), located in coding exon 23 of the CFTR gene, results from a G to T substitution at nucleotide position 3808. The aspartic acid at codon 1270 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in an individual diagnosed with cystic fibrosis however a second CFTR alteration was not documented (Raraigh KS et al. J Cyst Fibros, 2022 May;21:463-470). In an assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Feb;:). 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 the available evidence, the clinical significance of this variant remains unclear. -
ivacaftor response - Efficacy Other:1
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