rs149966534
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_017654.4(SAMD9):c.4586G>A(p.Arg1529His) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,613,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017654.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000921 AC: 14AN: 152076Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250822Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135566
GnomAD4 exome AF: 0.000137 AC: 200AN: 1461540Hom.: 0 Cov.: 33 AF XY: 0.000124 AC XY: 90AN XY: 727058
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152194Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Published functional studies suggest a damaging effect: increased cell growth suppression compared to wildtype (PMID: 34621053); Observed in a pediatric patient with myelodysplastic syndrome; however, it is not certain the variant was present in the germline (PMID: 34621053); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34621053, 28545555) -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1529 of the SAMD9 protein (p.Arg1529His). This variant is present in population databases (rs149966534, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with myelodysplastic syndrome (PMID: 34621053). ClinVar contains an entry for this variant (Variation ID: 521334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SAMD9 protein function. Experimental studies have shown that this missense change affects SAMD9 function (PMID: 34621053). 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. -
SAMD9: BP4, BS2 -
not specified Uncertain:1
DNA sequence analysis of the SAMD9 gene demonstrated a sequence change, c.4586G>A, in exon 3 that results in an amino acid change, p.Arg1529His. This sequence change does not appear to have been previously described in patients with SAMD9-related disorders and has been described in the gnomAD database with a low population frequency of 0.0085% (dbSNP rs149966534). The p.Arg1529His change affects a moderately conserved amino acid residue located in a domain of the SAMD9 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1529His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1529His change remains unknown at this time. -
Inborn genetic diseases Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at