7-117540171-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_000492.4(CFTR):c.941G>C(p.Gly314Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,744 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.941G>C | p.Gly314Ala | missense_variant | 8/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.941G>C | p.Gly314Ala | missense_variant | 8/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461744Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727172
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2022 | The p.G314A variant (also known as c.941G>C), located in coding exon 8 of the CFTR gene, results from a G to C substitution at nucleotide position 941. The glycine at codon 314 is replaced by alanine, an amino acid with similar properties. The G314 position is located in the fifth putative hydrophobic transmembrane domain of the CFTR protein. Other substitutions affecting the same codon, p.G314R and p.G314E, have been reported in individuals with cystic fibrosis or CFTR-related disorders; however, the clinical significance of these findings is unclear (Nasr SZ et al. Hum Mutat, 1996;7:151-4; Golla A et al. Hum Mutat, 1994;3:67-8). A functional study found this variant reduced the sensitivity of the chloride channel to activation (Mansoura MK et al. Biophys. J. 1998; 74:1320-32). This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2021 | This sequence change replaces glycine with alanine at codon 314 of the CFTR protein (p.Gly314Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 15371908). 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. This variant disrupts the p.Gly314 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 7509684, 8829633), which suggests that this may be a clinically significant amino acid residue. 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. - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 30, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at