rs35945487

Variant names:

• chr19-50907030-G-A
• rs35945487
• NM_004917.5:c.669C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50907030-G-A
• chr19-50907030-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The NM_004917.5(KLK4):​c.669C>T​(p.Phe223Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,614,132 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.012 (157 hom.)
• Consequence: KLK4 NM_004917.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 2A1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=-0.495 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1776/152268) while in subpopulation NFE AF = 0.0151 (1027/68020). AF 95% confidence interval is 0.0143. There are 19 homozygotes in GnomAd4. There are 941 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.669C>T	p.Phe223Phe	synonymous_variant	Exon 6 of 6	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.384C>T	p.Phe128Phe	synonymous_variant	Exon 5 of 5		NP_001289890.1
KLK4	NR_126566.2	n.658C>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.669C>T	p.Phe223Phe	synonymous_variant	Exon 6 of 6	1	NM_004917.5	ENSP00000326159.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1775 AN: 152150 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0119 AC: 3005 AN: 251476 AF XY: 0.0120

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0118 AC: 17313 AN: 1461864 Hom.: 157 Cov.: 32 AF XY: 0.0117 AC XY: 8542 AN XY: 727234

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.00660 AC: 295 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86258

European-Finnish (FIN) AF: 0.0466 AC: 2487 AN: 53420

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5762

European-Non Finnish (NFE) AF: 0.0122 AC: 13612 AN: 1111996

Other (OTH) AF: 0.0108 AC: 653 AN: 60392

GnomAD4 genome AF: 0.0117 AC: 1776 AN: 152268 Hom.: 19 Cov.: 32 AF XY: 0.0126 AC XY: 941 AN XY: 74456

African (AFR) AF: 0.00188 AC: 78 AN: 41548

American (AMR) AF: 0.00516 AC: 79 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0530 AC: 562 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1027 AN: 68020

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.0135 Hom.: 27

Bravo AF: 0.00767

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0122

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.39
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35945487; hg19: chr19-51410286; COSMIC: COSV60676678; COSMIC: COSV60676678;