7-117665554-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000492.4(CFTR):āc.4232A>Cā(p.Gln1411Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,608,898 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 Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Q1411Q) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 missense
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.4232A>C | p.Gln1411Pro | missense_variant | 26/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4232A>C | p.Gln1411Pro | missense_variant | 26/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250750Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135488
GnomAD4 exome AF: 0.00000618 AC: 9AN: 1456652Hom.: 0 Cov.: 28 AF XY: 0.00000414 AC XY: 3AN XY: 725080
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74380
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 12, 2022 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1411 of the CFTR protein (p.Gln1411Pro). This variant is present in population databases (rs150177304, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 495947). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2022 | The p.Q1411P variant (also known as c.4232A>C), located in coding exon 26 of the CFTR gene, results from an A to C substitution at nucleotide position 4232. The glutamine at codon 1411 is replaced by proline, an amino acid with similar properties. 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 alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2022 | Identified in computational analysis as a predicted variant of uncertain significance (Sanders et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32734384) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 21, 2016 | Variant summary: The c.4232A>C (p.Gln1411Pro) in CFTR gene is a missense change that involves a mildly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within AAA+ ATPase domain functional domain and several neighboring variants have been associated with CF, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.0000166 (2/120320 chrs tested), exclusively in individuals of Latino descent (0.00017; 2/11398) which does not exceed the maximal expected frequency of a pathogenic allele (0.013) in this gene. This variant was identified in a population screening of patients with primary sclerosing cholangitis and inflammatory bowel syndromes (Sickkids db). The variant has not, to our knowledge, been reported in affected individual via published reports or classified by a reputable database/clinical laboratory. At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at