4-166734943-T-C

Variant names:

• chr4-166734943-T-C
• rs1041625134
• NM_001040159.2:c.1280A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040159.2(SPOCK3):​c.1280A>G​(p.Asp427Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,178 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.174781).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040159.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOCK3	NM_001040159.2	MANE Select	c.1280A>G	p.Asp427Gly	missense	Exon 11 of 11	NP_001035249.1	Q9BQ16-1
	SPOCK3	NM_016950.3		c.1289A>G	p.Asp430Gly	missense	Exon 12 of 12	NP_058646.2	Q9BQ16-3
	SPOCK3	NM_001430594.1		c.1280A>G	p.Asp427Gly	missense	Exon 10 of 10	NP_001417523.1	Q9BQ16-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOCK3	ENST00000357545.9	TSL:1 MANE Select	c.1280A>G	p.Asp427Gly	missense	Exon 11 of 11	ENSP00000350153.4	Q9BQ16-1
	SPOCK3	ENST00000502330.5	TSL:1	c.1289A>G	p.Asp430Gly	missense	Exon 12 of 12	ENSP00000423606.1	Q9BQ16-3
	SPOCK3	ENST00000357154.7	TSL:5	c.1289A>G	p.Asp430Gly	missense	Exon 12 of 12	ENSP00000349677.3	Q9BQ16-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398178 Hom.: 0 Cov.: 24 AF XY: 0.00000143 AC XY: 1 AN XY: 698622

African (AFR) AF: 0.00 AC: 0 AN: 32610

American (AMR) AF: 0.00 AC: 0 AN: 44004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25530

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.00 AC: 0 AN: 83258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5290

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1056982

Other (OTH) AF: 0.00 AC: 0 AN: 58218

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.53
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0040	B
Vest4		0.22
MutPred		0.17		Gain of glycosylation at Y435 (P = 0.0158)
MVP		0.78
MPC		0.22
ClinPred		0.72	D
GERP RS		3.9
Varity_R		0.32
gMVP		0.33
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs1041625134; hg19: chr4-167656094;