rs34626614

chr19-50908495-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004917.5(KLK4):c.476G>A(p.Gly159Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,614,174 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (67 hom.)
• Consequence: KLK4 NM_004917.5 missense, splice_region
• Scores: Splicing: ADA: 0.07747
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0280

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029649138).
• BP6: Variant 19-50908495-C-T is Benign according to our data. Variant chr19-50908495-C-T is described in ClinVar as [Benign]. Clinvar id is 714810.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK4	NM_004917.5	c.476G>A	p.Gly159Asp	missense_variant, splice_region_variant	5/6	ENST00000324041.6
KLK4	NM_001302961.2	c.191G>A	p.Gly64Asp	missense_variant, splice_region_variant	4/5
KLK4	XM_011527545.4	c.476-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
KLK4	NR_126566.2	n.469-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK4	ENST00000324041.6	c.476G>A	p.Gly159Asp	missense_variant, splice_region_variant	5/6	1	NM_004917.5	P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2450 AN: 152180 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00420 AC: 1055 AN: 251414 Hom.: 28 AF XY: 0.00299 AC XY: 407 AN XY: 135900

Gnomad AFR exome AF: 0.0543

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1461876 Hom.: 67 Cov.: 32 AF XY: 0.00160 AC XY: 1166 AN XY: 727244

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.0162 AC: 2462 AN: 152298 Hom.: 59 Cov.: 32 AF XY: 0.0153 AC XY: 1141 AN XY: 74480

Gnomad4 AFR AF: 0.0551

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00335 Hom.: 16

Bravo AF: 0.0181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0576 AC: 254

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00511 AC: 621

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	D
Sift4G	Benign	0.064	T
Vest4		0.44
MVP		0.85
MPC		1.2
ClinPred		0.042	T
GERP RS		0.17
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.077
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.080		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: rs34626614; hg19: chr19-51411751;