chr4-166912633-G-C

Position:

• chr4-166912633-G-C

Variant summary

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

The NM_001040159.2(SPOCK3):​c.461C>G​(p.Thr154Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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	Protein	UniProt
SPOCK3	NM_001040159.2	c.461C>G	p.Thr154Ser	missense_variant	5/11	ENST00000357545.9	NP_001035249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOCK3	ENST00000357545.9	c.461C>G	p.Thr154Ser	missense_variant	5/11	1	NM_001040159.2	ENSP00000350153.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 01, 2024

The c.470C>G (p.T157S) alteration is located in exon 6 (coding exon 5) of the SPOCK3 gene. This alteration results from a C to G substitution at nucleotide position 470, causing the threonine (T) at amino acid position 157 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.033	.;T;.;.;.;T;T;.;.;T;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T;.;T;.;.;.;.;T;T;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.;.;.;L;L;.;.;L;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.0020	.;B;.;B;B;B;B;.;.;B;B;.;.
Vest4		0.21
MutPred		0.87		.;Gain of disorder (P = 0.0382);.;.;.;Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);.;.;Gain of disorder (P = 0.0382);.;.;.;
MVP		0.38
MPC		0.17
ClinPred		0.52	D
GERP RS		3.3
Varity_R		0.080
gMVP		0.50

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: chr4-167833784;