4-166734925-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040159.2(SPOCK3):c.1298T>A(p.Ile433Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00198 in 1,534,848 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (17 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.65

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006558448).
• BP6: Variant 4-166734925-A-T is Benign according to our data. Variant chr4-166734925-A-T is described in ClinVar as [Benign]. Clinvar id is 769638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1678/152058) while in subpopulation AFR AF= 0.0387 (1608/41536). AF 95% confidence interval is 0.0371. There are 30 homozygotes in gnomad4. There are 782 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.1298T>A	p.Ile433Asn	missense_variant	11/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.1298T>A	p.Ile433Asn	missense_variant	11/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1671 AN: 151940 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00278 AC: 654 AN: 235222 Hom.: 14 AF XY: 0.00193 AC XY: 247 AN XY: 127834

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.000531

GnomAD4 exome AF: 0.000981 AC: 1357 AN: 1382790 Hom.: 17 Cov.: 25 AF XY: 0.000835 AC XY: 576 AN XY: 689578

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000508

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000133

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.0110 AC: 1678 AN: 152058 Hom.: 30 Cov.: 32 AF XY: 0.0105 AC XY: 782 AN XY: 74344

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.00342

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00308 Hom.: 3

Bravo AF: 0.0125

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.56
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;.;T;.;.;.;.;T;T;T;D;T
MetaRNN	Benign	0.0066	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.75	D;D;D;D;D;D;D;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;.;D;D;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.99	.;D;.;D;D;D;D;.;.;D;.;D
Vest4		0.57
MVP		0.69
MPC		0.29
ClinPred		0.11	T
GERP RS		5.1
Varity_R		0.61
gMVP		0.36

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

Other links and lift over

dbSNP: rs75259705; hg19: chr4-167656076;