rs7255024

Variant names:

• chr19-50908007-C-A
• rs7255024
• NM_004917.5:c.612+352G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004917.5(KLK4):​c.612+352G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0683 in 398,964 control chromosomes in the GnomAD database, including 1,195 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 0.067 (376 hom., cov: 33)
  • Exomes 𝑓: 0.069 (819 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004917.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	NM_004917.5	MANE Select	c.612+352G>T		intron	N/A	NP_004908.4
	KLK4	NM_001302961.2		c.327+352G>T		intron	N/A	NP_001289890.1
	KLK4	NR_126566.2		n.601+352G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.612+352G>T		intron	N/A	ENSP00000326159.1	A0A0C4DFQ5
	KLK4	ENST00000431178.2	TSL:1	c.328+572G>T		intron	N/A	ENSP00000399448.2	Q9Y5K2-2
	KLK4	ENST00000596876.1	TSL:1	n.966G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10216 AN: 152060 Hom.: 376 Cov.: 33

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0627

Gnomad OTH AF: 0.0532

GnomAD4 exome AF: 0.0690 AC: 17026 AN: 246786 Hom.: 819 Cov.: 0 AF XY: 0.0752 AC XY: 9864 AN XY: 131152

African (AFR) AF: 0.0739 AC: 557 AN: 7540

American (AMR) AF: 0.0732 AC: 775 AN: 10584

Ashkenazi Jewish (ASJ) AF: 0.0721 AC: 503 AN: 6976

East Asian (EAS) AF: 0.0165 AC: 220 AN: 13362

South Asian (SAS) AF: 0.136 AC: 5155 AN: 37802

European-Finnish (FIN) AF: 0.0330 AC: 402 AN: 12166

Middle Eastern (MID) AF: 0.0625 AC: 60 AN: 960

European-Non Finnish (NFE) AF: 0.0595 AC: 8563 AN: 143886

Other (OTH) AF: 0.0585 AC: 791 AN: 13510

GnomAD4 genome AF: 0.0672 AC: 10226 AN: 152178 Hom.: 376 Cov.: 33 AF XY: 0.0677 AC XY: 5040 AN XY: 74406

African (AFR) AF: 0.0786 AC: 3263 AN: 41512

American (AMR) AF: 0.0741 AC: 1133 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 248 AN: 3470

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5180

South Asian (SAS) AF: 0.140 AC: 673 AN: 4816

European-Finnish (FIN) AF: 0.0270 AC: 286 AN: 10588

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0628 AC: 4268 AN: 68006

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0647 Hom.: 51

Bravo AF: 0.0689

Asia WGS AF: 0.0870 AC: 305 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.80
DANN	Benign	0.81
PhyloP100		-0.65
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: rs7255024; hg19: chr19-51411263;