rs121918554

Variant names:

• chr7-93101615-T-C
• rs121918554
• NM_017654.4:c.4483A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017654.4(SAMD9):​c.4483A>G​(p.Lys1495Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.12
• Publications: 11 publications found

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]

SAMD9 Gene-Disease associations (from GenCC):

• MIRAGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• normophosphatemic familial tumoral calcinosis

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• monosomy 7 myelodysplasia and leukemia syndrome 2

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-93101615-T-C is Pathogenic according to our data. Variant chr7-93101615-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1229.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD9	NM_017654.4	c.4483A>G	p.Lys1495Glu	missense_variant	Exon 3 of 3	ENST00000379958.3	NP_060124.2
SAMD9	NM_001193307.2	c.4483A>G	p.Lys1495Glu	missense_variant	Exon 2 of 2		NP_001180236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMD9	ENST00000379958.3	c.4483A>G	p.Lys1495Glu	missense_variant	Exon 3 of 3	1	NM_017654.4	ENSP00000369292.2
SAMD9	ENST00000620985.4	c.4483A>G	p.Lys1495Glu	missense_variant	Exon 2 of 2	2		ENSP00000484636.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Normophosphatemic familial tumoral calcinosis Pathogenic:1

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SAMD9 function (PMID: 16960814). Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 1229). This missense change has been observed in individual(s) with normophosphatemic familial tumoral calcinosis (PMID: 16960814, 18094730; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1495 of the SAMD9 protein (p.Lys1495Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T;.
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.90	P;P
Vest4		0.34
MutPred		0.55		Loss of MoRF binding (P = 0.0012);Loss of MoRF binding (P = 0.0012);
MVP		0.76
MPC		0.41
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.64
Mutation Taster		=29/71	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918554; hg19: chr7-92730928;