4-167000400-G-A

Variant summary

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

The NM_001040159.2(SPOCK3):c.299C>T(p.Ala100Val) 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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=0.12715393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.299C>T	p.Ala100Val	missense_variant	4/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.299C>T	p.Ala100Val	missense_variant	4/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455706 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 724268

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 29, 2021

The c.308C>T (p.A103V) alteration is located in exon 5 (coding exon 4) of the SPOCK3 gene. This alteration results from a C to T substitution at nucleotide position 308, causing the alanine (A) at amino acid position 103 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	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.014	T;.;.;.;T;T;.;.;T;.;.;.;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.;L;L;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.13	T;T;T;T;T;T;D;D;T;T;T;T;D;D
Sift4G	Uncertain	0.053	T;D;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.010	B;.;B;B;B;B;.;.;B;B;.;.;.;.
Vest4		0.14
MutPred		0.27		Loss of disorder (P = 0.085);.;.;.;Loss of disorder (P = 0.085);Loss of disorder (P = 0.085);.;.;Loss of disorder (P = 0.085);.;.;.;Loss of disorder (P = 0.085);Loss of disorder (P = 0.085);
MVP		0.45
MPC		0.17
ClinPred		0.45	T
GERP RS		2.7
Varity_R		0.062
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-167921551;