dbSNP rs706107: SPINK4:p.Val7Ile (chr9-33240227-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014471.3(SPINK4):c.19G>A(p.Val7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,604,088 control chromosomes in the GnomAD database, including 59,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 12043 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47525 hom. )

Consequence

SPINK4
NM_014471.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.657

Publications

22 publications found

Variant links:

Genes affected

SPINK4 (HGNC:16646): (serine peptidase inhibitor Kazal type 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity and response to xenobiotic stimulus. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

SPINK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.861092E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK4	NM_014471.3 link	c.19G>A	p.Val7Ile	missense_variant	Exon 1 of 4	ENST00000379721.4	NP_055286.1	O60575V9HWG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK4	ENST00000379721.4 link	c.19G>A	p.Val7Ile	missense_variant	Exon 1 of 4	1	NM_014471.3	ENSP00000369045.3		O60575
SPINK4	ENST00000379725.5 link	c.131-4885G>A		intron_variant	Intron 2 of 4	3		ENSP00000369048.1		Q5VZE7

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53584

AN:

151964

Hom.:

12034

Cov.:

show subpopulations

Gnomad AFR

AF:

0.643

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.297

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.256

Gnomad SAS

AF:

0.278

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.232

Gnomad OTH

AF:

0.332

GnomAD2 exomes

AF:

0.261

AC:

61843

AN:

237184

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.645

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.222

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.227

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.246

AC:

357443

AN:

1452006

Hom.:

47525

Cov.:

AF XY:

0.245

AC XY:

177141

AN XY:

721830

show subpopulations

African (AFR)

AF:

0.664

AC:

21752

AN:

32744

American (AMR)

AF:

0.252

AC:

11004

AN:

43642

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5820

AN:

25910

East Asian (EAS)

AF:

0.282

AC:

10922

AN:

38798

South Asian (SAS)

AF:

0.254

AC:

21530

AN:

84726

European-Finnish (FIN)

AF:

0.227

AC:

12046

AN:

53064

Middle Eastern (MID)

AF:

0.306

AC:

1759

AN:

5754

European-Non Finnish (NFE)

AF:

0.232

AC:

256455

AN:

1107380

Other (OTH)

AF:

0.269

AC:

16155

AN:

59988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

12664

25329

37993

50658

63322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8996

17992

26988

35984

44980

<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:

0.353

AC:

53641

AN:

152082

Hom.:

12043

Cov.:

AF XY:

0.347

AC XY:

25819

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.643

AC:

26678

AN:

41474

American (AMR)

AF:

0.296

AC:

4530

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

769

AN:

3470

East Asian (EAS)

AF:

0.256

AC:

1324

AN:

5162

South Asian (SAS)

AF:

0.277

AC:

1335

AN:

4824

European-Finnish (FIN)

AF:

0.220

AC:

2334

AN:

10588

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.232

AC:

15786

AN:

67968

Other (OTH)

AF:

0.330

AC:

696

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1563

3127

4690

6254

7817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.271

Hom.:

31315

Bravo

AF:

0.371

TwinsUK

AF:

0.224

AC:

830

ALSPAC

AF:

0.230

AC:

888

ESP6500AA

AF:

0.643

AC:

2832

ESP6500EA

AF:

0.234

AC:

2010

ExAC

AF:

0.268

AC:

32458

Asia WGS

AF:

0.325

AC:

1131

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.29

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0087

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0000039

MetaSVM

Benign

-0.95

PhyloP100

-0.66

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.080

REVEL

Benign

0.051

Sift

Benign

0.22

Sift4G

Benign

0.18

Polyphen

0.010

Vest4

0.062

MPC

0.063

ClinPred

0.0020

GERP RS

-7.2

PromoterAI

0.033

Neutral

(source)

Varity_R

0.023

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over