4-166734925-A-G

Variant names:

• chr4-166734925-A-G
• rs75259705
• NM_001040159.2:c.1298T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040159.2(SPOCK3):​c.1298T>C​(p.Ile433Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,382,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I433N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38519877).

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.1298T>C	p.Ile433Thr	missense	Exon 11 of 11	NP_001035249.1	Q9BQ16-1
	SPOCK3	NM_016950.3		c.1307T>C	p.Ile436Thr	missense	Exon 12 of 12	NP_058646.2	Q9BQ16-3
	SPOCK3	NM_001430594.1		c.1298T>C	p.Ile433Thr	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.1298T>C	p.Ile433Thr	missense	Exon 11 of 11	ENSP00000350153.4	Q9BQ16-1
	SPOCK3	ENST00000502330.5	TSL:1	c.1307T>C	p.Ile436Thr	missense	Exon 12 of 12	ENSP00000423606.1	Q9BQ16-3
	SPOCK3	ENST00000357154.7	TSL:5	c.1307T>C	p.Ile436Thr	missense	Exon 12 of 12	ENSP00000349677.3	Q9BQ16-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235222 AF XY: 0.00000782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382838 Hom.: 0 Cov.: 25 AF XY: 0.00000145 AC XY: 1 AN XY: 689600

African (AFR) AF: 0.00 AC: 0 AN: 31880

American (AMR) AF: 0.00 AC: 0 AN: 41324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38516

South Asian (SAS) AF: 0.00 AC: 0 AN: 78786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4864

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051930

Other (OTH) AF: 0.00 AC: 0 AN: 57550

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.62
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.82	P
Vest4		0.51
MutPred		0.30		Loss of stability (P = 9e-04)
MVP		0.80
MPC		0.21
ClinPred		0.35	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.21
Mutation Taster		=92/8	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: rs75259705; hg19: chr4-167656076;