19-50907019-G-A

Position:

• chr19-50907019-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004917.5(KLK4):​c.680C>T​(p.Pro227Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,146 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: KLK4 NM_004917.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -3.66

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0323534).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (244/152270) while in subpopulation NFE AF= 0.00272 (185/68012). AF 95% confidence interval is 0.0024. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK4	NM_004917.5	c.680C>T	p.Pro227Leu	missense_variant	6/6	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.395C>T	p.Pro132Leu	missense_variant	5/5		NP_001289890.1
KLK4	NR_126566.2	n.669C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.680C>T	p.Pro227Leu	missense_variant	6/6	1	NM_004917.5	ENSP00000326159.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00170 AC: 428 AN: 251488 Hom.: 1 AF XY: 0.00160 AC XY: 218 AN XY: 135916

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00237 AC: 3460 AN: 1461876 Hom.: 8 Cov.: 32 AF XY: 0.00234 AC XY: 1699 AN XY: 727244

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74448

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00124

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00161 AC: 196

EpiCase AF: 0.00256

EpiControl AF: 0.00243

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Male infertility Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	6.6
DANN	Benign	0.93
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.31	T
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.026	D
Vest4		0.19
MVP		0.53
MPC		0.45
ClinPred		0.10	T
GERP RS		-6.7
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs144350395; hg19: chr19-51410275;