19-50907860-T-C

Variant names:

• chr19-50907860-T-C
• rs1654553
• NM_004917.5:c.612+499A>G

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+499A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 234,838 control chromosomes in the GnomAD database, including 27,438 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 0.49 (18730 hom., cov: 33)
  • Exomes 𝑓: 0.44 (8708 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.612+499A>G		intron_variant	Intron 5 of 5	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.327+499A>G		intron_variant	Intron 4 of 4		NP_001289890.1
KLK4	NR_126566.2	n.601+499A>G		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.612+499A>G		intron_variant	Intron 5 of 5	1	NM_004917.5	ENSP00000326159.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74274 AN: 151938 Hom.: 18712 Cov.: 33

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.490

GnomAD4 exome AF: 0.436 AC: 36065 AN: 82782 Hom.: 8708 AF XY: 0.426 AC XY: 18229 AN XY: 42798

African (AFR) AF: 0.541 AC: 1279 AN: 2364

American (AMR) AF: 0.474 AC: 1848 AN: 3900

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1107 AN: 1952

East Asian (EAS) AF: 0.114 AC: 494 AN: 4326

South Asian (SAS) AF: 0.311 AC: 3563 AN: 11442

European-Finnish (FIN) AF: 0.464 AC: 1730 AN: 3726

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 23868 AN: 50446

Other (OTH) AF: 0.472 AC: 2044 AN: 4332

GnomAD4 genome AF: 0.489 AC: 74335 AN: 152056 Hom.: 18730 Cov.: 33 AF XY: 0.487 AC XY: 36189 AN XY: 74332

African (AFR) AF: 0.554 AC: 22987 AN: 41458

American (AMR) AF: 0.488 AC: 7464 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1908 AN: 3472

East Asian (EAS) AF: 0.114 AC: 590 AN: 5184

South Asian (SAS) AF: 0.318 AC: 1530 AN: 4818

European-Finnish (FIN) AF: 0.501 AC: 5281 AN: 10548

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32932 AN: 67976

Other (OTH) AF: 0.486 AC: 1026 AN: 2112

Alfa AF: 0.483 Hom.: 58539

Bravo AF: 0.493

Asia WGS AF: 0.228 AC: 797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.1
DANN	Benign	0.56
PhyloP100		0.43
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: rs1654553; hg19: chr19-51411116;