rs1554336981

chr7-93103178-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017654.4(SAMD9):c.2920G>A(p.Glu974Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E974E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 5.14

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-93103178-C-T is Pathogenic according to our data. Variant chr7-93103178-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 521232.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-93103178-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9	NM_017654.4	c.2920G>A	p.Glu974Lys	missense_variant	3/3	ENST00000379958.3
SAMD9	NM_001193307.2	c.2920G>A	p.Glu974Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9	ENST00000379958.3	c.2920G>A	p.Glu974Lys	missense_variant	3/3	1	NM_017654.4	P1
SAMD9	ENST00000620985.4	c.2920G>A	p.Glu974Lys	missense_variant	2/2	2		P1
SAMD9	ENST00000446617.1	c.2920G>A	p.Glu974Lys	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2016

Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -

MIRAGE syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.0054	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.56	N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.41
MutPred		0.54		Gain of methylation at E974 (P = 0.0016);Gain of methylation at E974 (P = 0.0016);Gain of methylation at E974 (P = 0.0016);
MVP		0.63
MPC		0.61
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554336981; hg19: chr7-92732491;