4-166737550-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040159.2(SPOCK3):c.1049A>G(p.His350Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

SPOCK3 (HGNC:13565): (SPARC (osteonectin), cwcv and kazal like domains proteoglycan 3) This gene encodes a member of a novel family of calcium-binding proteoglycan proteins that contain thyroglobulin type-1 and Kazal-like domains. The encoded protein and may play a role in adult T-cell leukemia by inhibiting the activity of membrane-type matrix metalloproteinases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.1049A>G	p.His350Arg	missense_variant	10/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.1049A>G	p.His350Arg	missense_variant	10/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460740 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726682

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.1058A>G (p.H353R) alteration is located in exon 11 (coding exon 10) of the SPOCK3 gene. This alteration results from a A to G substitution at nucleotide position 1058, causing the histidine (H) at amino acid position 353 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	0.19
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;.;T;.;.;.;.;T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.59	.;D;.;P;P;D;D;.;.;D;.;P
Vest4		0.37
MutPred		0.69		.;Loss of sheet (P = 0.0457);.;.;.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;.;Loss of sheet (P = 0.0457);.;.;
MVP		0.81
MPC		0.22
ClinPred		0.92	D
GERP RS		3.0
Varity_R		0.61
gMVP		0.67

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: rs1323387250; hg19: chr4-167658701;