rs1554336974

Positions:

• chr7-93103153-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R982C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-93103154-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 985307.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Pathogenic=3, Uncertain_significance=1}.
• 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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9	NM_017654.4	c.2945G>A	p.Arg982His	missense_variant	3/3	ENST00000379958.3
SAMD9	NM_001193307.2	c.2945G>A	p.Arg982His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9	ENST00000379958.3	c.2945G>A	p.Arg982His	missense_variant	3/3	1	NM_017654.4	P1
SAMD9	ENST00000620985.4	c.2945G>A	p.Arg982His	missense_variant	2/2	2		P1
SAMD9	ENST00000446617.1	c.2945G>A	p.Arg982His	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461546 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MIRAGE syndrome Pathogenic:3

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	- -
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 -

not provided Pathogenic:2

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. -
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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	0.54	D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.40	B;B;.
Vest4		0.28
MutPred		0.67		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		0.48
MPC		0.46
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.24
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554336974; hg19: chr7-92732466;