4-166734937-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040159.2(SPOCK3):c.1286A>G(p.His429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13243699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.1286A>G	p.His429Arg	missense_variant	11/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.1286A>G	p.His429Arg	missense_variant	11/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000205 AC: 5 AN: 243352 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1401556 Hom.: 0 Cov.: 25 AF XY: 0.00000286 AC XY: 2 AN XY: 699488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Nov 17, 2023

The c.1295A>G (p.H432R) alteration is located in exon 12 (coding exon 11) of the SPOCK3 gene. This alteration results from a A to G substitution at nucleotide position 1295, causing the histidine (H) at amino acid position 432 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	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	16
Dann	Benign	0.49
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;.;T;.;.;.;.;T;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	0.67	D;D;D;D;D;D;D;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.33	N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;B;B;B;.;.;B;.;B
Vest4		0.17
MutPred		0.23		.;Gain of glycosylation at Y435 (P = 0.0158);.;.;.;Gain of glycosylation at Y435 (P = 0.0158);Gain of glycosylation at Y435 (P = 0.0158);.;.;Gain of glycosylation at Y435 (P = 0.0158);.;.;
MVP		0.77
MPC		0.20
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.13

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: rs1283956740; hg19: chr4-167656088;