chr7-93102593-G-C

Variant names:

• chr7-93102593-G-C
• rs1554336918
• NM_017654.4:c.3505C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017654.4(SAMD9):​c.3505C>G​(p.Gln1169Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. Q1169R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13030437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD9	NM_017654.4	c.3505C>G	p.Gln1169Glu	missense_variant	Exon 3 of 3	ENST00000379958.3	NP_060124.2
SAMD9	NM_001193307.2	c.3505C>G	p.Gln1169Glu	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.3505C>G	p.Gln1169Glu	missense_variant	Exon 3 of 3	1	NM_017654.4	ENSP00000369292.2
SAMD9	ENST00000620985.4	c.3505C>G	p.Gln1169Glu	missense_variant	Exon 2 of 2	2		ENSP00000484636.1
SAMD9	ENST00000446617.1	c.3505C>G	p.Gln1169Glu	missense_variant	Exon 2 of 2	2		ENSP00000414529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3505C>G (p.Q1169E) alteration is located in exon 3 (coding exon 1) of the SAMD9 gene. This alteration results from a C to G substitution at nucleotide position 3505, causing the glutamine (Q) at amino acid position 1169 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.50
DEOGEN2	Benign	0.0065	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.56	T;.;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		3.6
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	.;N;N
REVEL	Benign	0.078
Sift	Benign	0.46	.;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.023	B;B;.
Vest4		0.30
MutPred		0.27		Gain of phosphorylation at S1166 (P = 0.113);Gain of phosphorylation at S1166 (P = 0.113);Gain of phosphorylation at S1166 (P = 0.113);
MVP		0.53
MPC		0.23
ClinPred		0.22	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.19
Mutation Taster		=73/27	polymorphism

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: rs1554336918; hg19: chr7-92731906;