7-93101374-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017654.4(SAMD9):c.4724G>A(p.Gly1575Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00168 in 1,613,358 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1575R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 3 hom. )

Consequence

SAMD9
NM_017654.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 5.51

Publications

4 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, Ambry Genetics
SAMD9-related spectrum and myeloid neoplasm risk
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
normophosphatemic familial tumoral calcinosis
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen
monosomy 7 myelodysplasia and leukemia syndrome 2
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

SAMD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05644813).

BP6

Variant 7-93101374-C-T is Benign according to our data. Variant chr7-93101374-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 709973.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0012 (183/152038) while in subpopulation NFE AF = 0.00134 (91/67942). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	NM_017654.4	MANE Select	c.4724G>A	p.Gly1575Glu	missense	Exon 3 of 3	NP_060124.2
	SAMD9	NM_001193307.2		c.4724G>A	p.Gly1575Glu	missense	Exon 2 of 2	NP_001180236.1	Q5K651

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD9	ENST00000379958.3	TSL:1 MANE Select	c.4724G>A	p.Gly1575Glu	missense	Exon 3 of 3	ENSP00000369292.2	Q5K651
	SAMD9	ENST00000620985.4	TSL:2	c.4724G>A	p.Gly1575Glu	missense	Exon 2 of 2	ENSP00000484636.1	Q5K651

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00166

AC:

418

AN:

251144

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00813

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00173

AC:

2522

AN:

1461320

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1213

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00863

AC:

459

AN:

53196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00178

AC:

1975

AN:

1111730

Other (OTH)

AF:

0.00116

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152038

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.000338

AC:

AN:

41426

American (AMR)

AF:

0.000524

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000890

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00175

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Normophosphatemic familial tumoral calcinosis;C4284088:MIRAGE syndrome;C5436668:Monosomy 7 myelodysplasia and leukemia syndrome 2 (1)

not specified (1)

SAMD9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.039

MetaRNN

Benign

0.056

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.5

PhyloP100

5.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.82

MVP

0.87

MPC

0.75

ClinPred

0.077

GERP RS

4.4

Varity_R

0.89

gMVP

0.95

Mutation Taster

=42/58

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over