7-93105103-A-G

Position:

• chr7-93105103-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.995T>C​(p.Ile332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,696 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: SAMD9 NM_017654.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.978

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=0.0028614402).
• BP6: Variant 7-93105103-A-G is Benign according to our data. Variant chr7-93105103-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1872/152050) while in subpopulation AFR AF= 0.0427 (1770/41484). AF 95% confidence interval is 0.041. There are 43 homozygotes in gnomad4. There are 909 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAMD9	NM_017654.4	c.995T>C	p.Ile332Thr	missense_variant	3/3	ENST00000379958.3	NP_060124.2
SAMD9	NM_001193307.2	c.995T>C	p.Ile332Thr	missense_variant	2/2		NP_001180236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAMD9	ENST00000379958.3	c.995T>C	p.Ile332Thr	missense_variant	3/3	1	NM_017654.4	ENSP00000369292.2
SAMD9	ENST00000620985.4	c.995T>C	p.Ile332Thr	missense_variant	2/2	2		ENSP00000484636.1
SAMD9	ENST00000446617.1	c.995T>C	p.Ile332Thr	missense_variant	2/2	2		ENSP00000414529.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1873 AN: 151934 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00492

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: 0.0000736

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00315 AC: 791 AN: 250976 Hom.: 18 AF XY: 0.00232 AC XY: 315 AN XY: 135644

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00126 AC: 1838 AN: 1461646 Hom.: 39 Cov.: 35 AF XY: 0.00103 AC XY: 752 AN XY: 727112

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.0123 AC: 1872 AN: 152050 Hom.: 43 Cov.: 33 AF XY: 0.0122 AC XY: 909 AN XY: 74334

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00222 Hom.: 14

Bravo AF: 0.0142

ESP6500AA AF: 0.0440 AC: 194

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.24
DANN	Benign	0.49
DEOGEN2	Benign	0.00074	T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.23	T;.;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	.;N;N
REVEL	Benign	0.014
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.023
MVP		0.048
MPC		0.19
ClinPred		0.0033	T
GERP RS		-4.1
Varity_R		0.029
gMVP		0.077

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: rs76377166; hg19: chr7-92734416; COSMIC: COSV99060850;