rs76377166

Variant names:

• chr7-93105103-A-G
• rs76377166
• NM_017654.4:c.995T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017654.4(SAMD9):​c.995T>C​(p.Ile332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,696 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I332I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.978
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028614402).
• BP6: Variant 7-93105103-A-G is Benign according to our data. Variant chr7-93105103-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1872/152050) while in subpopulation AFR AF = 0.0427 (1770/41484). AF 95% confidence interval is 0.041. There are 43 homozygotes in GnomAd4. There are 909 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,AD,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	NM_017654.4	MANE Select	c.995T>C	p.Ile332Thr	missense	Exon 3 of 3	NP_060124.2
	SAMD9	NM_001193307.2		c.995T>C	p.Ile332Thr	missense	Exon 2 of 2	NP_001180236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	ENST00000379958.3	TSL:1 MANE Select	c.995T>C	p.Ile332Thr	missense	Exon 3 of 3	ENSP00000369292.2
	SAMD9	ENST00000620985.4	TSL:2	c.995T>C	p.Ile332Thr	missense	Exon 2 of 2	ENSP00000484636.1
	SAMD9	ENST00000446617.1	TSL:2	c.995T>C	p.Ile332Thr	missense	Exon 2 of 2	ENSP00000414529.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1873 AN: 151934 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00315 AC: 791 AN: 250976 AF XY: 0.00232

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00126 AC: 1838 AN: 1461646 Hom.: 39 Cov.: 35 AF XY: 0.00103 AC XY: 752 AN XY: 727112

African (AFR) AF: 0.0451 AC: 1508 AN: 33472

American (AMR) AF: 0.00250 AC: 112 AN: 44712

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111902

Other (OTH) AF: 0.00290 AC: 175 AN: 60394

GnomAD4 genome AF: 0.0123 AC: 1872 AN: 152050 Hom.: 43 Cov.: 33 AF XY: 0.0122 AC XY: 909 AN XY: 74334

African (AFR) AF: 0.0427 AC: 1770 AN: 41484

American (AMR) AF: 0.00491 AC: 75 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.00475 Hom.: 28

Bravo AF: 0.0142

ESP6500AA AF: 0.0440 AC: 194

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.24
DANN	Benign	0.49
DEOGEN2	Benign	0.00074	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.98
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.014
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MVP		0.048
MPC		0.19
ClinPred		0.0033	T
GERP RS		-4.1
Varity_R		0.029
gMVP		0.077
Mutation Taster		=97/3	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: rs76377166; hg19: chr7-92734416; COSMIC: COSV99060850;