4-166734943-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.1280A>G(p.Asp427Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000014 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

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=0.174781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.1280A>G	p.Asp427Gly	missense_variant	11/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.1280A>G	p.Asp427Gly	missense_variant	11/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398178 Hom.: 0 Cov.: 24 AF XY: 0.00000143 AC XY: 1 AN XY: 698622

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: 0.00000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 27, 2022

The c.1289A>G (p.D430G) 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 1289, causing the aspartic acid (D) at amino acid position 430 to be replaced by a glycine (G). 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	0.093
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.53
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T;.;T;.;.;.;.;T;T;T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.51	N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0040, 0.0060	.;B;.;B;B;B;B;.;.;B;.;B
Vest4		0.22
MutPred		0.17		.;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		0.78
MPC		0.22
ClinPred		0.72	D
GERP RS		3.9
Varity_R		0.32
gMVP		0.33

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: rs1041625134; hg19: chr4-167656094;