chr7-93103153-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_017654.4(SAMD9):c.2945G>A(p.Arg982His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SAMD9
NM_017654.4 missense
NM_017654.4 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 1.41
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 Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-93103153-C-T is Pathogenic according to our data. Variant chr7-93103153-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SAMD9 | ENST00000379958.3 | c.2945G>A | p.Arg982His | missense_variant | 3/3 | 1 | NM_017654.4 | ENSP00000369292.2 | ||
SAMD9 | ENST00000620985.4 | c.2945G>A | p.Arg982His | missense_variant | 2/2 | 2 | ENSP00000484636.1 | |||
SAMD9 | ENST00000446617.1 | c.2945G>A | p.Arg982His | missense_variant | 2/2 | 2 | ENSP00000414529.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461546Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727090
GnomAD4 exome
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AC:
3
AN:
1461546
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Cov.:
33
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1
AN XY:
727090
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MIRAGE syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | May 15, 2020 | ACMG codes: PS2, PS3, PM2, PP4 - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic and Treatment Unit for Congenital Metabolic Diseases, Hopital Clínico Universitario de Santiago de Compostela (CHUS) | Nov 10, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Published functional studies suggest a damaging effect: gain of function variant resulting in decreased cell proliferation (Buonocore et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 31231135, 29217778, 28346228, 34258490, 34930662, 28545555, 27535533) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 14, 2021 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 982 of the SAMD9 protein (p.Arg982His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been observed in individual(s) with clinical features of MIRAGE syndrome (PMID: 28346228, 31231135, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 559913). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg982 amino acid residue in SAMD9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28346228). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;.;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;D
REVEL
Benign
Sift
Pathogenic
.;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
B;B;.
Vest4
MutPred
Gain of catalytic residue at H985 (P = 0.2967);Gain of catalytic residue at H985 (P = 0.2967);Gain of catalytic residue at H985 (P = 0.2967);
MVP
MPC
0.46
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at