4-167000374-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001040159.2(SPOCK3):c.325A>G(p.Ile109Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,592,230 control chromosomes in the GnomAD database, including 469 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (254 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (215 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.307

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=0.0021817386).
• BP6: Variant 4-167000374-T-C is Benign according to our data. Variant chr4-167000374-T-C is described in ClinVar as [Benign]. Clinvar id is 769639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK3	NM_001040159.2	c.325A>G	p.Ile109Val	missense_variant	4/11	ENST00000357545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK3	ENST00000357545.9	c.325A>G	p.Ile109Val	missense_variant	4/11	1	NM_001040159.2	A2

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4636 AN: 152152 Hom.: 253 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

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: 0.000265

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.00787 AC: 1915 AN: 243418 Hom.: 98 AF XY: 0.00592 AC XY: 780 AN XY: 131712

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00302 AC: 4342 AN: 1439960 Hom.: 215 Cov.: 26 AF XY: 0.00262 AC XY: 1878 AN XY: 717172

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000765

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00667

GnomAD4 genome AF: 0.0305 AC: 4641 AN: 152270 Hom.: 254 Cov.: 33 AF XY: 0.0298 AC XY: 2215 AN XY: 74442

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.00922 Hom.: 108

Bravo AF: 0.0354

ESP6500AA AF: 0.0994 AC: 438

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00978 AC: 1187

Asia WGS AF: 0.00837 AC: 30 AN: 3478

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	0.069
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	2.0
Dann	Benign	0.51
DEOGEN2	Benign	0.0074	T;.;.;.;T;T;.;.;T;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.47	N
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;.;.;.;L;L;.;.;L;.;.;.;.;.
MutationTaster	Benign	0.96	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.10	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.86	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.0070	B;.;B;B;B;B;.;.;B;B;.;.;.;.
Vest4		0.056
MVP		0.15
MPC		0.14
ClinPred		0.0047	T
GERP RS		-3.7
Varity_R		0.033
gMVP		0.17

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: rs9685645; hg19: chr4-167921525;