19-50980251-G-A

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.458C>T(p.Thr153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

KLK7
NM_005046.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.578

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:

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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=0.023258686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK7	NM_005046.4 link	c.458C>T	p.Thr153Met	missense_variant	Exon 4 of 6	ENST00000595820.6	NP_005037.1	P49862-1A0A024R4H6B4DHX9
KLK7	NM_139277.2 link	c.458C>T	p.Thr153Met	missense_variant	Exon 4 of 6		NP_644806.1	P49862-1A0A024R4H6
KLK7	NM_001243126.1 link	c.437C>T	p.Thr146Met	missense_variant	Exon 3 of 5		NP_001230055.1	P49862B4DHX9
KLK7	NM_001207053.2 link	c.242C>T	p.Thr81Met	missense_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.458C>T	p.Thr153Met	missense_variant	Exon 4 of 6	1	NM_005046.4	ENSP00000470538.1		P49862-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000387

AC:

AN:

250524

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00627

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00593

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000342

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000795

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000329

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.458C>T (p.T153M) alteration is located in exon 4 (coding exon 3) of the KLK7 gene. This alteration results from a C to T substitution at nucleotide position 458, causing the threonine (T) at amino acid position 153 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.090

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.71

T;.;T

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.0

D;.;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

D;.;.

Sift4G

Uncertain

0.0020

D;D;T

Polyphen

1.0

D;D;.

Vest4

0.33

MVP

0.95

MPC

0.24

ClinPred

0.047

GERP RS

2.0

Varity_R

0.31

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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