19-50980241-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005046.4(KLK7):c.468T>A(p.Asp156Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KLK7
NM_005046.4 missense, splice_region

Scores

Splicing: ADA: 0.0001642

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.86

Variant links:

Genes affected

KLK7 (HGNC:6368): (kallikrein related peptidase 7) This gene encodes a member of the kallikrein subfamily of serine proteases. These enzymes have diverse physiological functions and many kallikrein genes are biomarkers for cancer. The encoded protein has chymotrypsin-like activity and plays a role in the proteolysis of intercellular cohesive structures that precedes desquamation, the shedding of the outermost layer of the epidermis. The encoded protein may play a role in cancer invasion and metastasis, and increased expression of this gene is associated with unfavorable prognosis and progression of several types of cancer. Polymorphisms in this gene may play a role in the development of atopic dermatitis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, which is one of fifteen kallikrein subfamily members located in a gene cluster on chromosome 19. [provided by RefSeq, May 2011]

KLK7 links:

ENSG00000267879 (HGNC:):

ENSG00000267879 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044299573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK7	NM_005046.4 link	c.468T>A	p.Asp156Glu	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000595820.6	NP_005037.1	P49862-1A0A024R4H6B4DHX9
KLK7	NM_139277.2 link	c.468T>A	p.Asp156Glu	missense_variant, splice_region_variant	Exon 4 of 6		NP_644806.1	P49862-1A0A024R4H6
KLK7	NM_001243126.1 link	c.447T>A	p.Asp149Glu	missense_variant, splice_region_variant	Exon 3 of 5		NP_001230055.1	P49862B4DHX9
KLK7	NM_001207053.2 link	c.252T>A	p.Asp84Glu	missense_variant, splice_region_variant	Exon 3 of 5		NP_001193982.1	P49862-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6 link	c.468T>A	p.Asp156Glu	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_005046.4	ENSP00000470538.1		P49862-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250144

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000616

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000793

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.468T>A (p.D156E) alteration is located in exon 4 (coding exon 3) of the KLK7 gene. This alteration results from a T to A substitution at nucleotide position 468, causing the aspartic acid (D) at amino acid position 156 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.018

DANN

Benign

0.62

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.025

T;.;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.14

N;N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.17

N;.;.

REVEL

Benign

0.19

Sift

Benign

0.15

T;.;.

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.093

MutPred

0.32

Gain of catalytic residue at D156 (P = 0.1273);Gain of catalytic residue at D156 (P = 0.1273);.;

MVP

0.45

MPC

0.030

ClinPred

0.0066

GERP RS

-8.4

Varity_R

0.22

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over