19-50906547-C-T

Variant names:

• chr19-50906547-C-T
• rs1654556
• NM_004917.5:c.*387G>A

Variant summary

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

The NM_004917.5(KLK4):​c.*387G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.85 (41152 hom., cov: 14)
  • Exomes 𝑓: 0.83 (44669 hom.)
• Consequence: KLK4 NM_004917.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 3 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.929 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.*387G>A		3_prime_UTR	Exon 6 of 6	NP_004908.4
	KLK4	NM_001302961.2		c.*387G>A		3_prime_UTR	Exon 5 of 5	NP_001289890.1
	KLK4	NR_126566.2		n.1141G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.*387G>A		3_prime_UTR	Exon 6 of 6	ENSP00000326159.1	A0A0C4DFQ5
	KLK4	ENST00000597441.1	TSL:3	n.65G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.846 AC: 94732 AN: 112004 Hom.: 41141 Cov.: 14

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.833

Gnomad MID AF: 0.945

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.868

GnomAD4 exome AF: 0.826 AC: 103270 AN: 125064 Hom.: 44669 Cov.: 0 AF XY: 0.820 AC XY: 54678 AN XY: 66662

African (AFR) AF: 0.934 AC: 2429 AN: 2600

American (AMR) AF: 0.839 AC: 5180 AN: 6176

Ashkenazi Jewish (ASJ) AF: 0.921 AC: 2976 AN: 3230

East Asian (EAS) AF: 0.132 AC: 618 AN: 4680

South Asian (SAS) AF: 0.772 AC: 15484 AN: 20050

European-Finnish (FIN) AF: 0.851 AC: 5307 AN: 6238

Middle Eastern (MID) AF: 0.935 AC: 391 AN: 418

European-Non Finnish (NFE) AF: 0.870 AC: 65571 AN: 75386

Other (OTH) AF: 0.845 AC: 5314 AN: 6286

GnomAD4 genome AF: 0.846 AC: 94764 AN: 112046 Hom.: 41152 Cov.: 14 AF XY: 0.842 AC XY: 45349 AN XY: 53880

African (AFR) AF: 0.938 AC: 26227 AN: 27956

American (AMR) AF: 0.830 AC: 9430 AN: 11364

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 2587 AN: 2882

East Asian (EAS) AF: 0.196 AC: 728 AN: 3716

South Asian (SAS) AF: 0.719 AC: 2209 AN: 3072

European-Finnish (FIN) AF: 0.833 AC: 5802 AN: 6962

Middle Eastern (MID) AF: 0.936 AC: 204 AN: 218

European-Non Finnish (NFE) AF: 0.851 AC: 45660 AN: 53670

Other (OTH) AF: 0.859 AC: 1303 AN: 1516

Alfa AF: 0.864 Hom.: 5438

Bravo AF: 0.852

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.67
PhyloP100		-1.6
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1654556; hg19: chr19-51409803;