Variant 4-166735009-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040159.2(SPOCK3):c.1214T>C(p.Ile405Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000833 in 1,560,692 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: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

SPOCK3
NM_001040159.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

Variant links:

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]

SPOCK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0155668855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2 linkuse as main transcript	c.1214T>C	p.Ile405Thr	missense_variant	11/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9 linkuse as main transcript	c.1214T>C	p.Ile405Thr	missense_variant	11/11	1	NM_001040159.2	A2	Q9BQ16-1

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000117

AC:

AN:

247250

Hom.:

AF XY:

0.0000747

AC XY:

AN XY:

133930

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000497

AC:

AN:

1408802

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

704058

show subpopulations

Gnomad4 AFR exome

AF:

0.00181

Gnomad4 AMR exome

AF:

0.0000225

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:

9.40e-7

Gnomad4 OTH exome

AF:

0.000153

GnomAD4 genome

AF:

0.000395

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000470

Hom.:

Bravo

AF:

0.000461

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2024

The c.1223T>C (p.I408T) alteration is located in exon 12 (coding exon 11) of the SPOCK3 gene. This alteration results from a T to C substitution at nucleotide position 1223, causing the isoleucine (I) at amino acid position 408 to be replaced by a threonine (T). 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

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.013

.;T;.;.;.;T;T;.;.;T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

T;.;T;.;.;.;.;T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.016

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.1

.;M;.;.;.;M;M;.;.;M;.;.

MutationTaster

Benign

0.71

D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.070

N;N;N;N;N;N;N;.;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.11

T;T;T;T;T;T;T;.;T;T;T;T

Sift4G

Benign

0.63

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.18, 0.28

.;B;.;B;B;B;B;.;.;B;.;B

Vest4

0.18

MVP

0.88

MPC

0.21

ClinPred

0.050

GERP RS

5.0

Varity_R

0.11

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over