rs397508621
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_000492.4(CFTR):āc.3872A>Gā(p.Gln1291Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,460,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. Q1291H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000492.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3872A>G | p.Gln1291Arg | missense_variant, splice_region_variant | 23/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3872A>G | p.Gln1291Arg | missense_variant, splice_region_variant | 23/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.65+4759T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250580Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135428
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460994Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726774
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2019 | The p.Q1291R variant (also known as c.3872A>G), located in coding exon 23 of the CFTR gene, results from an A to G substitution at nucleotide position 3872. The glutamine at codon 1291 is replaced by arginine, an amino acid with highly similar properties. This variant was identified in conjunction with p.F508del in an individual with pancreatic insufficient cystic fibrosis (CF) (Dörk T et al. Hum. Genet., 1994 Nov;94:533-42). In a cohort of individuals with CF and CFTR-related disorders, this variant was detected in the homozygous state; however, clinical information was not provided (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403). This variant was also detected in conjunction with p.F508del in an individual with abnormal newborn screening, equivocal sweat chloride results, and an abnormal nasal potential difference (Sermet-Gaudelus I et al. Thorax, 2010 Jun;65:539-44). It was the only variant identified in an individual with congenital bilateral absence of the vas deferens (Bienvenu T et al. Hum. Genet., 1995 Jun;95:698-702). Analysis of a rectal biopsy from an individual with this variant demonstrated aberrant splicing from the Q1291R allele due to use of a cryptic splice site and resulting in the inclusion of 29 base pairs and predicted to create a premature stop codon (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7). Functional analysis of this variant in CFBE cells demonstrated 62% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). The p.Q1291R alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). 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 available evidence to date, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 15, 2023 | Variant summary: CFTR c.3872A>G (p.Gln1291Arg) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these splicing predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250580 control chromosomes (gnomAD). c.3872A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (e.g. Doerk_1994, Lucarelli_2015). These data indicate that the variant is very likely to be associated with disease. Functional assays using CFTR deficient Bronchial Epithelial cells showed the variant had 62.3% residual activity, with the authors concluding the variant had varying clinical consequences (Rareigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 7525450, 25910067, 29805046). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jul 24, 2015 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 02, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at