7-93101365-A-G

Position:

chr7-93101365-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017654.4(SAMD9):c.4733T>C(p.Ile1578Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00835 in 1,613,408 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 64 hom. )

Consequence

SAMD9
NM_017654.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.82

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003968388).

BP6

Variant 7-93101365-A-G is Benign according to our data. Variant chr7-93101365-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 769723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00626 (953/152242) while in subpopulation NFE AF= 0.00946 (643/67956). AF 95% confidence interval is 0.00886. There are 6 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMD9	NM_017654.4 linkuse as main transcript	c.4733T>C	p.Ile1578Thr	missense_variant	3/3	ENST00000379958.3	NP_060124.2	Q5K651
SAMD9	NM_001193307.2 linkuse as main transcript	c.4733T>C	p.Ile1578Thr	missense_variant	2/2		NP_001180236.1	Q5K651

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMD9	ENST00000379958.3 linkuse as main transcript	c.4733T>C	p.Ile1578Thr	missense_variant	3/3	1	NM_017654.4	ENSP00000369292.2		Q5K651
SAMD9	ENST00000620985.4 linkuse as main transcript	c.4733T>C	p.Ile1578Thr	missense_variant	2/2	2		ENSP00000484636.1		Q5K651

Frequencies

GnomAD3 genomes

AF:

0.00626

AC:

952

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00946

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00572

AC:

1437

AN:

251060

Hom.:

AF XY:

0.00580

AC XY:

787

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00317

Gnomad NFE exome

AF:

0.00983

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00857

AC:

12526

AN:

1461166

Hom.:

Cov.:

AF XY:

0.00821

AC XY:

5970

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.00501

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00405

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.00717

GnomAD4 genome

AF:

0.00626

AC:

953

AN:

152242

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

398

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00946

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00789

Hom.:

Bravo

AF:

0.00633

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.00627

AC:

761

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SAMD9: BP4, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 20, 2017

- -

SAMD9-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SAMD9 NM_017654.3 exon 3 p.Ile1578Thr (c.4733T>C): This variant has not been reported in the literature but is present in 0.09% (643/67964) of European alleles including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-93101365-A-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:769723). This variant amino acid Threonine (Thr) is present in 3 species (Pig, Tasmanian Devil, Opossum) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0098

T;T

Eigen

Benign

-0.083

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.64

T;.

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

.;N

REVEL

Benign

0.057

Sift

Benign

0.12

.;T

Sift4G

Benign

0.26

T;T

Polyphen

0.034

B;B

Vest4

0.29

MVP

0.40

MPC

0.20

ClinPred

0.012

GERP RS

3.3

Varity_R

0.034

gMVP

0.76

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