4-166735009-A-G

Variant names:

• chr4-166735009-A-G
• rs144307556
• NM_001040159.2:c.1214T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040159.2(SPOCK3):​c.1214T>C​(p.Ile405Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000833 in 1,560,692 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SPOCK3 NM_001040159.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0155668855).

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.1214T>C	p.Ile405Thr	missense	Exon 11 of 11	NP_001035249.1	Q9BQ16-1
	SPOCK3	NM_016950.3		c.1223T>C	p.Ile408Thr	missense	Exon 12 of 12	NP_058646.2	Q9BQ16-3
	SPOCK3	NM_001430594.1		c.1214T>C	p.Ile405Thr	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.1214T>C	p.Ile405Thr	missense	Exon 11 of 11	ENSP00000350153.4	Q9BQ16-1
	SPOCK3	ENST00000502330.5	TSL:1	c.1223T>C	p.Ile408Thr	missense	Exon 12 of 12	ENSP00000423606.1	Q9BQ16-3
	SPOCK3	ENST00000357154.7	TSL:5	c.1223T>C	p.Ile408Thr	missense	Exon 12 of 12	ENSP00000349677.3	Q9BQ16-3

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 247250 AF XY: 0.0000747

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000497 AC: 70 AN: 1408802 Hom.: 0 Cov.: 24 AF XY: 0.0000426 AC XY: 30 AN XY: 704058

African (AFR) AF: 0.00181 AC: 59 AN: 32590

American (AMR) AF: 0.0000225 AC: 1 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39274

South Asian (SAS) AF: 0.00 AC: 0 AN: 84842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 9.40e-7 AC: 1 AN: 1064256

Other (OTH) AF: 0.000153 AC: 9 AN: 58704

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151890 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74232

African (AFR) AF: 0.00137 AC: 57 AN: 41492

American (AMR) AF: 0.0000658 AC: 1 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67874

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.000461

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.60
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.084
Sift	Benign	0.11	T
Sift4G	Benign	0.63	T
Polyphen		0.18	B
Vest4		0.18
MVP		0.88
MPC		0.21
ClinPred		0.050	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.31
Mutation Taster		=78/22	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: rs144307556; hg19: chr4-167656160;