rs198966

chr19-50908754-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004917.5(KLK4):c.300C>T(p.Ser100=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,614,014 control chromosomes in the GnomAD database, including 503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (250 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (253 hom.)
• Consequence: KLK4 NM_004917.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0190

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-50908754-G-A is Benign according to our data. Variant chr19-50908754-G-A is described in ClinVar as [Benign]. Clinvar id is 782657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK4	NM_004917.5	c.300C>T	p.Ser100=	synonymous_variant	4/6	ENST00000324041.6
KLK4	NM_001302961.2	c.15C>T	p.Ser5=	synonymous_variant	3/5
KLK4	XM_011527545.4	c.300C>T	p.Ser100=	synonymous_variant	3/4
KLK4	NR_126566.2	n.293C>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK4	ENST00000324041.6	c.300C>T	p.Ser100=	synonymous_variant	4/6	1	NM_004917.5	P1

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4713 AN: 152056 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00804 AC: 2019 AN: 251164 Hom.: 97 AF XY: 0.00616 AC XY: 837 AN XY: 135826

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00344 AC: 5022 AN: 1461840 Hom.: 253 Cov.: 32 AF XY: 0.00299 AC XY: 2177 AN XY: 727228

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000298

Gnomad4 OTH exome AF: 0.00715

GnomAD4 genome AF: 0.0311 AC: 4731 AN: 152174 Hom.: 250 Cov.: 32 AF XY: 0.0297 AC XY: 2206 AN XY: 74376

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0161 Hom.: 71

Bravo AF: 0.0362

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.54

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: rs198966; hg19: chr19-51412010;