chr19-50979901-A-T

Position:

• chr19-50979901-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005046.4(KLK7):​c.493T>A​(p.Cys165Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK7	NM_005046.4	c.493T>A	p.Cys165Ser	missense_variant	5/6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.493T>A	p.Cys165Ser	missense_variant	5/6		NP_644806.1
KLK7	NM_001243126.1	c.472T>A	p.Cys158Ser	missense_variant	4/5		NP_001230055.1
KLK7	NM_001207053.2	c.277T>A	p.Cys93Ser	missense_variant	4/5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.493T>A	p.Cys165Ser	missense_variant	5/6	1	NM_005046.4	ENSP00000470538	P1
	ENST00000594512.1	n.297+6568A>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.493T>A (p.C165S) alteration is located in exon 5 (coding exon 4) of the KLK7 gene. This alteration results from a T to A substitution at nucleotide position 493, causing the cysteine (C) at amino acid position 165 to be replaced by a serine (S). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.59	T;.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.74	N;N;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-9.5	D;.;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.55
MutPred		0.80		Gain of disorder (P = 0.0176);Gain of disorder (P = 0.0176);.;
MVP		0.88
MPC		0.26
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.89
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51483157;