rs1654551

chr19-50909412-A-C

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.64T>G(p.Ser22Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,798 control chromosomes in the GnomAD database, including 6,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 1/1 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S22W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1464 hom., cov: 31)
  • Exomes 𝑓: 0.081 (5503 hom.)
• Consequence: KLK4 NM_004917.5 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50

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=0.0026489794).
• BP6: Variant 19-50909412-A-C is Benign according to our data. Variant chr19-50909412-A-C is described in ClinVar as [Benign]. Clinvar id is 1258657.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-50909412-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK4	NM_004917.5	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	3/6	ENST00000324041.6
KLK4	XM_011527545.4	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	2/4
KLK4	NM_001302961.2	c.-234T>G		splice_region_variant, 5_prime_UTR_variant	2/5
KLK4	NR_126566.2	n.62-17T>G		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.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	3/6	1	NM_004917.5	P1
KLK4	ENST00000602148.1	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant, NMD_transcript_variant	2/5	1
KLK4	ENST00000598305.5	c.-217-17T>G		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
KLK4	ENST00000596876.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18000 AN: 152060 Hom.: 1456 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.0943

GnomAD3 exomes AF: 0.0881 AC: 22104 AN: 250912 Hom.: 1189 AF XY: 0.0889 AC XY: 12067 AN XY: 135728

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0568

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.0833

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0812 AC: 118722 AN: 1461620 Hom.: 5503 Cov.: 36 AF XY: 0.0819 AC XY: 59582 AN XY: 727086

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0470

Gnomad4 ASJ exome AF: 0.0582

Gnomad4 EAS exome AF: 0.0996

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.0743

Gnomad4 OTH exome AF: 0.0921

GnomAD4 genome AF: 0.119 AC: 18046 AN: 152178 Hom.: 1464 Cov.: 31 AF XY: 0.118 AC XY: 8779 AN XY: 74402

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.0651

Gnomad4 ASJ AF: 0.0622

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0792

Gnomad4 NFE AF: 0.0743

Gnomad4 OTH AF: 0.0943

Alfa AF: 0.0931 Hom.: 484

Bravo AF: 0.124

TwinsUK AF: 0.0804 AC: 298

ALSPAC AF: 0.0698 AC: 269

ESP6500AA AF: 0.212 AC: 933

ESP6500EA AF: 0.0716 AC: 616

ExAC AF: 0.0922 AC: 11194

Asia WGS AF: 0.0990 AC: 344 AN: 3478

EpiCase AF: 0.0709

EpiControl AF: 0.0735

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

GeneDx

Jun 09, 2021

This variant is associated with the following publications: (PMID: 22970239) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	3.9
Dann	Benign	0.50
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.18
Sift	Benign	0.76	T
Sift4G	Benign	0.91	T
Vest4		0.028
MPC		0.28
ClinPred		0.0088	T
GERP RS		-7.0
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1654551; hg19: chr19-51412668; COSMIC: COSV60675801; COSMIC: COSV60675801;