Genetic Variant SPOCK3:p.Ile433Asn (chr4-166734925-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040159.2(SPOCK3):c.1298T>A(p.Ile433Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00198 in 1,534,848 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I433V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 17 hom. )

Consequence

SPOCK3
NM_001040159.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.65

Publications

0 publications found

Variant links:

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]

SPOCK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006558448).

BP6

Variant 4-166734925-A-T is Benign according to our data. Variant chr4-166734925-A-T is described in ClinVar as Benign. ClinVar VariationId is 769638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1678/152058) while in subpopulation AFR AF = 0.0387 (1608/41536). AF 95% confidence interval is 0.0371. There are 30 homozygotes in GnomAd4. There are 782 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPOCK3	NM_001040159.2	MANE Select	c.1298T>A	p.Ile433Asn	missense	Exon 11 of 11	NP_001035249.1	Q9BQ16-1
SPOCK3	NM_016950.3		c.1307T>A	p.Ile436Asn	missense	Exon 12 of 12	NP_058646.2	Q9BQ16-3
SPOCK3	NM_001430594.1		c.1298T>A	p.Ile433Asn	missense	Exon 10 of 10	NP_001417523.1	Q9BQ16-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPOCK3	ENST00000357545.9	TSL:1 MANE Select	c.1298T>A	p.Ile433Asn	missense	Exon 11 of 11	ENSP00000350153.4	Q9BQ16-1
SPOCK3	ENST00000502330.5	TSL:1	c.1307T>A	p.Ile436Asn	missense	Exon 12 of 12	ENSP00000423606.1	Q9BQ16-3
SPOCK3	ENST00000357154.7	TSL:5	c.1307T>A	p.Ile436Asn	missense	Exon 12 of 12	ENSP00000349677.3	Q9BQ16-3

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1671

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00342

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:

0.0000442

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00278

AC:

654

AN:

235222

AF XY:

0.00193

show subpopulations

Gnomad AFR exome

AF:

0.0401

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000930

Gnomad OTH exome

AF:

0.000531

GnomAD4 exome

AF:

0.000981

AC:

1357

AN:

1382790

Hom.:

Cov.:

AF XY:

0.000835

AC XY:

576

AN XY:

689578

show subpopulations

African (AFR)

AF:

0.0360

AC:

1147

AN:

31838

American (AMR)

AF:

0.00143

AC:

AN:

41324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25208

East Asian (EAS)

AF:

0.00

AC:

AN:

38516

South Asian (SAS)

AF:

0.0000508

AC:

AN:

78786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52780

Middle Eastern (MID)

AF:

0.00185

AC:

AN:

4862

European-Non Finnish (NFE)

AF:

0.0000133

AC:

AN:

1051928

Other (OTH)

AF:

0.00215

AC:

124

AN:

57548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0110

AC:

1678

AN:

152058

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

782

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0387

AC:

1608

AN:

41536

American (AMR)

AF:

0.00342

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67896

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.0125

ESP6500AA

AF:

0.0390

AC:

172

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00365

AC:

443

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.050

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.5

PhyloP100

6.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.57

MVP

0.69

MPC

0.29

ClinPred

0.11

GERP RS

5.1

Varity_R

0.61

gMVP

0.36

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over