rs1554337424

chr7-93105965-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017654.4(SAMD9):c.132del(p.Val45SerfsTer2) variant causes a frameshift 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A44A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9 NM_017654.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.950

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-93105965-CT-C is Pathogenic according to our data. Variant chr7-93105965-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556683.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9	NM_017654.4	c.132del	p.Val45SerfsTer2	frameshift_variant	3/3	ENST00000379958.3
SAMD9	NM_001193307.2	c.132del	p.Val45SerfsTer2	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9	ENST00000379958.3	c.132del	p.Val45SerfsTer2	frameshift_variant	3/3	1	NM_017654.4	P1
SAMD9	ENST00000620985.4	c.132del	p.Val45SerfsTer2	frameshift_variant	2/2	2		P1
SAMD9	ENST00000446617.1	c.132del	p.Val45SerfsTer2	frameshift_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Normophosphatemic familial tumoral calcinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs1554337424; hg19: chr7-92735278;