4-166737475-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040159.2(SPOCK3):c.1124C>T(p.Ala375Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41121963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.1124C>T	p.Ala375Val	missense_variant	10/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.1124C>T	p.Ala375Val	missense_variant	10/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 29, 2023

The c.1133C>T (p.A378V) alteration is located in exon 11 (coding exon 10) of the SPOCK3 gene. This alteration results from a C to T substitution at nucleotide position 1133, causing the alanine (A) at amino acid position 378 to be replaced by a valine (V). 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	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Benign	0.68
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;.;D;.;.;.;.;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.99	N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.60	T;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.38, 0.11	.;B;.;B;B;B;B;.;.;B;.;B
Vest4		0.15
MutPred		0.74		.;Loss of catalytic residue at A378 (P = 0.065);.;.;.;Loss of catalytic residue at A378 (P = 0.065);Loss of catalytic residue at A378 (P = 0.065);.;.;Loss of catalytic residue at A378 (P = 0.065);.;.;
MVP		0.86
MPC		0.27
ClinPred		0.33	T
GERP RS		4.6
Varity_R		0.076
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-167658626;