NM_004917.5:c.476G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004917.5(KLK4):c.476G>A(p.Gly159Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,174 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 59 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 67 hom. )

Consequence

KLK4
NM_004917.5 missense, splice_region

Scores

Splicing: ADA: 0.07747

Clinical Significance

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

Conservation

PhyloP100: -0.0280

Publications

8 publications found

Variant links:

Genes affected

KLK4 (HGNC:6365): (kallikrein related peptidase 4) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Dec 2014]

KLK4 Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 2A1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.031208 (below the threshold of 3.09). Trascript score misZ: -0.079907 (below the threshold of 3.09). GenCC associations: The gene is linked to amelogenesis imperfecta type 2, amelogenesis imperfecta type 2A1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029649138).

BP6

Variant 19-50908495-C-T is Benign according to our data. Variant chr19-50908495-C-T is described in ClinVar as Benign. ClinVar VariationId is 714810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5 link	c.476G>A	p.Gly159Asp	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000324041.6	NP_004908.4	Q9Y5K2A0A0C4DFQ5
KLK4	NM_001302961.2 link	c.191G>A	p.Gly64Asp	missense_variant, splice_region_variant	Exon 4 of 5		NP_001289890.1	Q9Y5K2Q5BQA0
KLK4	NR_126566.2 link	n.469-4G>A		splice_region_variant, intron_variant	Intron 3 of 4
KLK4	XM_011527545.4 link	c.476-4G>A		splice_region_variant, intron_variant	Intron 3 of 3		XP_011525847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6 link	c.476G>A	p.Gly159Asp	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_004917.5	ENSP00000326159.1		A0A0C4DFQ5

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2450

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00420

AC:

1055

AN:

251414

AF XY:

0.00299

show subpopulations

Gnomad AFR exome

AF:

0.0543

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00186

AC:

2720

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1166

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0593

AC:

1984

AN:

33480

American (AMR)

AF:

0.00342

AC:

153

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000255

AC:

284

AN:

1112010

Other (OTH)

AF:

0.00449

AC:

271

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

197

394

592

789

986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.0162

AC:

2462

AN:

152298

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1141

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0551

AC:

2287

AN:

41538

American (AMR)

AF:

0.00751

AC:

115

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68030

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

109

218

326

435

544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00638

Hom.:

Bravo

AF:

0.0181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0576

AC:

254

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00511

AC:

621

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.50

M_CAP

Benign

0.037

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.72

PhyloP100

-0.028

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.021

Sift4G

Benign

0.064

Vest4

0.44

MVP

0.85

MPC

1.2

ClinPred

0.042

GERP RS

0.17

gMVP

0.79

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.077

dbscSNV1_RF

Benign

0.35

SpliceAI score (max)

0.080

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over