5-137112517-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004598.4(SPOCK1):c.392C>G(p.Ser131Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S131L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPOCK1 NM_004598.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

SPOCK1 (HGNC:11251): (SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1) This gene encodes the protein core of a seminal plasma proteoglycan containing chondroitin- and heparan-sulfate chains. The protein's function is unknown, although similarity to thyropin-type cysteine protease-inhibitors suggests its function may be related to protease inhibition. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3227193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK1	NM_004598.4	c.392C>G	p.Ser131Trp	missense_variant	5/11	ENST00000394945.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK1	ENST00000394945.6	c.392C>G	p.Ser131Trp	missense_variant	5/11	1	NM_004598.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251246 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461514 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727026

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Apr 11, 2023

The c.392C>G (p.S131W) alteration is located in exon 5 (coding exon 4) of the SPOCK1 gene. This alteration results from a C to G substitution at nucleotide position 392, causing the serine (S) at amino acid position 131 to be replaced by a tryptophan (W). 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	0.21
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D;.;N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.46
MutPred		0.49		Loss of disorder (P = 0.006);.;Loss of disorder (P = 0.006);
MVP		0.72
MPC		0.83
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.50

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: rs146503135; hg19: chr5-136448206;