chr4-166742020-C-T

Variant summary

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

The NM_001040159.2(SPOCK3):​c.971G>A​(p.Arg324Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,612,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

SPOCK3
NM_001040159.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48
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]

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=0.02345571).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPOCK3NM_001040159.2 linkuse as main transcriptc.971G>A p.Arg324Gln missense_variant 9/11 ENST00000357545.9 NP_001035249.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPOCK3ENST00000357545.9 linkuse as main transcriptc.971G>A p.Arg324Gln missense_variant 9/111 NM_001040159.2 ENSP00000350153 A2Q9BQ16-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
151996
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000590
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000378
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
250896
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135596
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.000555
Gnomad NFE exome
AF:
0.000124
Gnomad OTH exome
AF:
0.000654
GnomAD4 exome
AF:
0.0000753
AC:
110
AN:
1460658
Hom.:
0
Cov.:
29
AF XY:
0.0000839
AC XY:
61
AN XY:
726698
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.000162
Gnomad4 FIN exome
AF:
0.000468
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152112
Hom.:
1
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000378
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000240
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000247
AC:
30
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsAug 22, 2023The c.980G>A (p.R327Q) alteration is located in exon 10 (coding exon 9) of the SPOCK3 gene. This alteration results from a G to A substitution at nucleotide position 980, causing the arginine (R) at amino acid position 327 to be replaced by a glutamine (Q). 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
0.060
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
15
DANN
Benign
0.52
DEOGEN2
Benign
0.0066
.;T;.;.;.;T;T;.;.;T;.;.
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.89
D;.;D;.;.;.;.;D;D;D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.023
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-1.3
.;N;.;.;.;N;N;.;.;N;.;.
MutationTaster
Benign
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.20
N;N;N;N;N;N;N;.;N;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.64
T;T;T;T;T;T;T;.;T;T;T;T
Sift4G
Benign
0.58
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.064, 0.024
.;B;.;B;B;B;B;.;.;B;.;B
Vest4
0.098
MVP
0.69
MPC
0.20
ClinPred
0.018
T
GERP RS
3.1
Varity_R
0.031
gMVP
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs138814470; hg19: chr4-167663171; COSMIC: COSV62736939; API