rs754308821
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020937.4(FANCM):c.1706G>A(p.Arg569His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,418 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. R569C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020937.4 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 |
---|---|---|---|---|---|---|---|
FANCM | NM_020937.4 | c.1706G>A | p.Arg569His | missense_variant | 10/23 | ENST00000267430.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCM | ENST00000267430.10 | c.1706G>A | p.Arg569His | missense_variant | 10/23 | 1 | NM_020937.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251354Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135864
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461418Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727040
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 03, 2021 | DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.1706G>A, in exon 10 that results in an amino acid change, p.Arg569His. This sequence change does not appear to have been previously described in patients with FANCM-related disorders. This sequence change has been described in the gnomAD database with a low frequency of 0.020% in the south Asian subpopulation (dbSNP rs754308821). The p.Arg569His change affects a highly conserved amino acid residue located in a domain of the FANCM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg569His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg569His change remains unknown at this time. - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 05, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 526406). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. This variant is present in population databases (rs754308821, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 569 of the FANCM protein (p.Arg569His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at