16-89765061-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_000135.4(FANCA):c.2607G>C(p.Gln869His) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q869P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000135.4 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 |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2607G>C | p.Gln869His | missense_variant | 28/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.2607G>C | p.Gln869His | missense_variant | 28/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.2607G>C | p.Gln869His | missense_variant | 28/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 03, 2017 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Gln869Pro) has been reported in individuals affected with Fanconi anemia in the literature (PMID: 15643609) and in the Leiden Open-source Variation Database (PMID: 21520333), however, in some of these individuals, a second FANCA variant was not identified. In addition, an experimental study demonstrates that this variant may disrupt FANCA protein complex formation with FANCB and FANCL (PMID: 16720839). This suggests that the glutamine residue is may be critical for FANCA protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCA-related disease. This sequence change replaces glutamine with histidine at codon 869 of the FANCA protein (p.Gln869His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at