rs149966534
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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
Genomes: 𝑓 0.000099 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
SAMD9
NM_017654.4 missense
NM_017654.4 missense
Scores
1
4
11
Clinical Significance
Conservation
PhyloP100: 4.61
Genes affected
SAMD9 (HGNC:1348): (sterile alpha motif domain containing 9) This gene encodes a sterile alpha motif domain-containing protein. The encoded protein localizes to the cytoplasm and may play a role in regulating cell proliferation and apoptosis. Mutations in this gene are the cause of normophosphatemic familial tumoral calcinosis. Alternate splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.36752832).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAMD9 | NM_017654.4 | c.4586G>A | p.Arg1529His | missense_variant | 3/3 | ENST00000379958.3 | |
SAMD9 | NM_001193307.2 | c.4586G>A | p.Arg1529His | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAMD9 | ENST00000379958.3 | c.4586G>A | p.Arg1529His | missense_variant | 3/3 | 1 | NM_017654.4 | P1 | |
SAMD9 | ENST00000620985.4 | c.4586G>A | p.Arg1529His | missense_variant | 2/2 | 2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000921 AC: 14AN: 152076Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250822Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135566
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GnomAD4 exome AF: 0.000137 AC: 200AN: 1461540Hom.: 0 Cov.: 33 AF XY: 0.000124 AC XY: 90AN XY: 727058
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GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152194Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74424
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: increased cell growth suppression compared to wildtype (Sahoo et al., 2021); Observed in a pediatric patient with myelodysplastic syndrome; however, it is not certain the variant was present in the germline (Sahoo et al., 2021); This variant is associated with the following publications: (PMID: 28545555, 34621053) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | 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). 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 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. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | SAMD9: BP4, BS2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 17, 2020 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N
PrimateAI
Benign
T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MVP
MPC
0.21
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at