rs375515095

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1BP6BS1

The NM_017654.4(SAMD9):c.1800_1801delAA(p.Glu600AspfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,613,508 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

SAMD9
NM_017654.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.241

Publications

0 publications found

Variant links:

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

SAMD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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 36 pathogenic variants in the truncated region.

BP6

Variant 7-93104296-ATT-A is Benign according to our data. Variant chr7-93104296-ATT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554815.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00233 (354/152250) while in subpopulation AFR AF = 0.00828 (344/41564). AF 95% confidence interval is 0.00756. There are 1 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD9	NM_017654.4 link	c.1800_1801delAA	p.Glu600AspfsTer12	frameshift_variant	Exon 3 of 3	ENST00000379958.3	NP_060124.2	Q5K651
SAMD9	NM_001193307.2 link	c.1800_1801delAA	p.Glu600AspfsTer12	frameshift_variant	Exon 2 of 2		NP_001180236.1	Q5K651

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SAMD9	ENST00000379958.3 link	c.1800_1801delAA	p.Glu600AspfsTer12	frameshift_variant	Exon 3 of 3	1	NM_017654.4	ENSP00000369292.2	Q5K651
SAMD9	ENST00000620985.4 link	c.1800_1801delAA	p.Glu600AspfsTer12	frameshift_variant	Exon 2 of 2	2		ENSP00000484636.1	Q5K651
SAMD9	ENST00000446617.1 link	c.1800_1801delAA	p.Glu600AspfsTer12	frameshift_variant	Exon 2 of 2	2		ENSP00000414529.1	C9JKF1

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

352

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00825

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000527

AC:

132

AN:

250676

AF XY:

0.000347

show subpopulations

Gnomad AFR exome

AF:

0.00776

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000213

AC:

311

AN:

1461258

Hom.:

AF XY:

0.000183

AC XY:

133

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.00829

AC:

277

AN:

33432

American (AMR)

AF:

0.000201

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111724

Other (OTH)

AF:

0.000348

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00233

AC:

354

AN:

152250

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00828

AC:

344

AN:

41564

American (AMR)

AF:

0.000261

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67968

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00258

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Mar 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 990 amino acids are replaced with 11 different amino acids with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28346228, 28545555) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SAMD9-related disorder

Uncertain:1

Dec 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SAMD9 c.1800_1801delAA variant is predicted to result in a frameshift and premature protein termination (p.Glu600Aspfs*12). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.78% of alleles in individuals of African descent in gnomAD. This variant has been reported with conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/554815/). Although we suspect that this variant is likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Normophosphatemic familial tumoral calcinosis

Uncertain:1

Nov 03, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

Mutation Taster

=64/136

disease causing (ClinVar)

(source)

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

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rs375515095

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over