rs748026786
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000492.4(CFTR):c.610G>A(p.Ala204Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A204S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.610G>A | p.Ala204Thr | missense_variant | 6/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.610G>A | p.Ala204Thr | missense_variant | 6/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000200 AC: 3AN: 150328Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251424Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727210
GnomAD4 genome ? AF: 0.0000200 AC: 3AN: 150328Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1AN XY: 73432
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 204 of the CFTR protein (p.Ala204Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis (PMID: 19017867). ClinVar contains an entry for this variant (Variation ID: 555386). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 19017867). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2023 | Variant summary: CFTR c.610G>A (p.Ala204Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.610G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Mutesa_2009) . These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. One publication reports weak expression and altered glycosylation (Mutesa_2009), however, does not allow convincing conclusions about the variant effect. The following publication have been ascertained in the context of this evaluation (PMID: 19017867). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at