7-93101374-C-A

Variant names:

• chr7-93101374-C-A
• rs148724199
• NM_017654.4:c.4724G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017654.4(SAMD9):​c.4724G>T​(p.Gly1575Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1575E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51
• Publications: 4 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, Ambry Genetics
• SAMD9-related spectrum and myeloid neoplasm risk

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• normophosphatemic familial tumoral calcinosis

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

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017654.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	NM_017654.4	MANE Select	c.4724G>T	p.Gly1575Val	missense	Exon 3 of 3	NP_060124.2
	SAMD9	NM_001193307.2		c.4724G>T	p.Gly1575Val	missense	Exon 2 of 2	NP_001180236.1	Q5K651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	ENST00000379958.3	TSL:1 MANE Select	c.4724G>T	p.Gly1575Val	missense	Exon 3 of 3	ENSP00000369292.2	Q5K651
	SAMD9	ENST00000620985.4	TSL:2	c.4724G>T	p.Gly1575Val	missense	Exon 2 of 2	ENSP00000484636.1	Q5K651

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.65		Loss of disorder (P = 0.3385)
MVP		0.85
MPC		0.74
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.89
gMVP		0.92
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs148724199; hg19: chr7-92730687;