7-93101360-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_017654.4(SAMD9):​c.4738G>A​(p.Gly1580Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G1580G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SAMD9
NM_017654.4 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SAMD9NM_017654.4 linkc.4738G>A p.Gly1580Ser missense_variant Exon 3 of 3 ENST00000379958.3 NP_060124.2 Q5K651
SAMD9NM_001193307.2 linkc.4738G>A p.Gly1580Ser missense_variant Exon 2 of 2 NP_001180236.1 Q5K651

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SAMD9ENST00000379958.3 linkc.4738G>A p.Gly1580Ser missense_variant Exon 3 of 3 1 NM_017654.4 ENSP00000369292.2 Q5K651
SAMD9ENST00000620985.4 linkc.4738G>A p.Gly1580Ser missense_variant Exon 2 of 2 2 ENSP00000484636.1 Q5K651

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251022
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461028
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726852
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152058
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

SAMD9-related disorder Uncertain:1
Jan 17, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SAMD9 c.4738G>A variant is predicted to result in the amino acid substitution p.Gly1580Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0047% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1
Dec 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G1580S variant (also known as c.4738G>A), located in coding exon 1 of the SAMD9 gene, results from a G to A substitution at nucleotide position 4738. The glycine at codon 1580 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1
Oct 29, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1580 of the SAMD9 protein (p.Gly1580Ser). This variant is present in population databases (rs776490364, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SAMD9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1987222). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SAMD9 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;.
M_CAP
Benign
0.035
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-4.8
.;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.75
MutPred
0.59
Gain of disorder (P = 0.1132);Gain of disorder (P = 0.1132);
MVP
0.87
MPC
0.66
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.88
gMVP
0.92

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.

Other links and lift over

dbSNP: rs776490364; hg19: chr7-92730673; API