chr19-50980251-G-A

Position:

• chr19-50980251-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.578

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_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/exons	MANE	Protein	UniProt
KLK7	NM_005046.4	c.458C>T	p.Thr153Met	missense_variant	4/6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.458C>T	p.Thr153Met	missense_variant	4/6		NP_644806.1
KLK7	NM_001243126.1	c.437C>T	p.Thr146Met	missense_variant	3/5		NP_001230055.1
KLK7	NM_001207053.2	c.242C>T	p.Thr81Met	missense_variant	3/5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.458C>T	p.Thr153Met	missense_variant	4/6	1	NM_005046.4	ENSP00000470538	P1
	ENST00000594512.1	n.297+6918G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152060 Hom.: 0 Cov.: 29

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: 97 AN: 250524 Hom.: 1 AF XY: 0.000303 AC XY: 41 AN XY: 135520

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.: 0 Cov.: 33 AF XY: 0.000197 AC XY: 143 AN XY: 727168

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: 52 AN: 152178 Hom.: 0 Cov.: 29 AF XY: 0.000376 AC XY: 28 AN XY: 74374

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.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.00115 AC: 4 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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

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

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T;.;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.76	N;N;N
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs112070660; hg19: chr19-51483507;