chr19-50906507-G-T

Variant names:

• chr19-50906507-G-T
• rs1139132
• NM_004917.5:c.*427C>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.*427C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 237,216 control chromosomes in the GnomAD database, including 11,440 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 0.36 (9962 hom., cov: 22)
  • Exomes 𝑓: 0.12 (1478 hom.)
• Consequence: KLK4 NM_004917.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.*427C>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000324041.6	NP_004908.4
KLK4	NR_126566.2	n.1181C>A		non_coding_transcript_exon_variant	Exon 5 of 5
KLK4	NM_001302961.2	c.*427C>A		3_prime_UTR_variant	Exon 5 of 5		NP_001289890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.*427C>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000597441.1	n.105C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.364 AC: 49250 AN: 135418 Hom.: 9950 Cov.: 22

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.118 AC: 12016 AN: 101730 Hom.: 1478 Cov.: 0 AF XY: 0.115 AC XY: 6180 AN XY: 53820

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.176 AC: 347 AN: 1974

American (AMR) AF: 0.141 AC: 756 AN: 5362

Ashkenazi Jewish (ASJ) AF: 0.0777 AC: 220 AN: 2830

East Asian (EAS) AF: 0.0510 AC: 262 AN: 5142

South Asian (SAS) AF: 0.129 AC: 1924 AN: 14906

European-Finnish (FIN) AF: 0.104 AC: 529 AN: 5094

Middle Eastern (MID) AF: 0.147 AC: 48 AN: 326

European-Non Finnish (NFE) AF: 0.120 AC: 7310 AN: 60892

Other (OTH) AF: 0.119 AC: 620 AN: 5204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.364 AC: 49274 AN: 135486 Hom.: 9962 Cov.: 22 AF XY: 0.359 AC XY: 23634 AN XY: 65882

African (AFR) AF: 0.453 AC: 16193 AN: 35724

American (AMR) AF: 0.328 AC: 4499 AN: 13708

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1024 AN: 3190

East Asian (EAS) AF: 0.155 AC: 745 AN: 4796

South Asian (SAS) AF: 0.385 AC: 1578 AN: 4098

European-Finnish (FIN) AF: 0.292 AC: 2697 AN: 9232

Middle Eastern (MID) AF: 0.384 AC: 93 AN: 242

European-Non Finnish (NFE) AF: 0.347 AC: 21473 AN: 61804

Other (OTH) AF: 0.367 AC: 674 AN: 1838

Alfa AF: 0.341 Hom.: 963

Asia WGS AF: 0.177 AC: 551 AN: 3100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.29
PhyloP100		0.038
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: rs1139132; hg19: chr19-51409763;