rs397508221
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000492.4(CFTR):c.1501A>G(p.Thr501Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T501I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1501A>G | p.Thr501Ala | missense_variant | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1161T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1501A>G | p.Thr501Ala | missense_variant | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:1Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Sep 30, 2021 | the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 10, 2024 | Variant summary: CFTR c.1501A>G (p.Thr501Ala) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 251300 control chromosomes (gnomAD). c.1501A>G has been reported in the literature in at least one homozygous individual affected with Cystic Fibrosis, and in at least two CF cohorts without additional genotype information (e.g. Claustres, 2000, Schrijver_2005, Petrova_2020). Additionally, it has been found in the heterozygous state in two individuals with CBAVD (Lu_2014). These data indicate that the variant may be associated with disease. It has been reported that an in vitro study of this variant revealed no CFTR mature protein, however this finding is unpublished and therefore the data is not available for review (Claustres_2017). The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 24559724, 32429104, 15858154, 28603918). ClinVar contains an entry for this variant (Variation ID: 53270). 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