7-93101365-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. I1578I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (64 hom.)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.82

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]

ACMG classification

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 GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD9	NM_017654.4	c.4733T>C	p.Ile1578Thr	missense_variant	3/3	ENST00000379958.3
SAMD9	NM_001193307.2	c.4733T>C	p.Ile1578Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD9	ENST00000379958.3	c.4733T>C	p.Ile1578Thr	missense_variant	3/3	1	NM_017654.4	P1
SAMD9	ENST00000620985.4	c.4733T>C	p.Ile1578Thr	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 952 AN: 152124 Hom.: 6 Cov.: 32

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.: 5 AF XY: 0.00580 AC XY: 787 AN XY: 135718

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.: 64 Cov.: 32 AF XY: 0.00821 AC XY: 5970 AN XY: 726910

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.: 6 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74450

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.: 3

Bravo AF: 0.00633

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00627 AC: 761

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SAMD9: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0098	T;T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T;.
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.87	D
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.26	T;T
Polyphen		0.034	B;B
Vest4		0.29
MVP		0.40
MPC		0.20
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs144380633; hg19: chr7-92730678; COSMIC: COSV66073354; COSMIC: COSV66073354;