rs149966534

Positions:

chr7-93101512-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_017654.4(SAMD9):c.4586G>A(p.Arg1529His) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,613,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SAMD9
NM_017654.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.61

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36752832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMD9	NM_017654.4 linkuse as main transcript	c.4586G>A	p.Arg1529His	missense_variant	3/3	ENST00000379958.3	NP_060124.2
SAMD9	NM_001193307.2 linkuse as main transcript	c.4586G>A	p.Arg1529His	missense_variant	2/2		NP_001180236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMD9	ENST00000379958.3 linkuse as main transcript	c.4586G>A	p.Arg1529His	missense_variant	3/3	1	NM_017654.4	ENSP00000369292	P1
SAMD9	ENST00000620985.4 linkuse as main transcript	c.4586G>A	p.Arg1529His	missense_variant	2/2	2		ENSP00000484636	P1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.0000877

AC:

AN:

250822

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

200

AN:

1461540

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1529 of the SAMD9 protein (p.Arg1529His). This variant is present in population databases (rs149966534, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with myelodysplastic syndrome (PMID: 34621053). ClinVar contains an entry for this variant (Variation ID: 521334). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SAMD9 function (PMID: 34621053). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SAMD9: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2024	Published functional studies suggest a damaging effect: increased cell growth suppression compared to wildtype (PMID: 34621053); Observed in a pediatric patient with myelodysplastic syndrome; however, it is not certain the variant was present in the germline (PMID: 34621053); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34621053, 28545555) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 17, 2020

DNA sequence analysis of the SAMD9 gene demonstrated a sequence change, c.4586G>A, in exon 3 that results in an amino acid change, p.Arg1529His. This sequence change does not appear to have been previously described in patients with SAMD9-related disorders and has been described in the gnomAD database with a low population frequency of 0.0085% (dbSNP rs149966534). The p.Arg1529His change affects a moderately conserved amino acid residue located in a domain of the SAMD9 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1529His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1529His change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.69

T;.

M_CAP

Benign

0.0042

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.89

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.0

.;D

REVEL

Benign

0.18

Sift

Uncertain

0.028

.;D

Sift4G

Benign

0.072

T;T

Polyphen

1.0

D;D

Vest4

0.19

MVP

0.66

MPC

0.21

ClinPred

0.73

GERP RS

4.3

Varity_R

0.085

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over