rs73042387

Variant names:

• chr19-50906915-G-A
• rs73042387
• ENST00000598305.5:n.*279C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000598305.5(KLK4):​n.*279C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,344 control chromosomes in the GnomAD database, including 14,700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1148 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13552 hom.)
• Consequence: KLK4 ENST00000598305.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.110
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-50906915-G-A is Benign according to our data. Variant chr19-50906915-G-A is described in ClinVar as Benign. ClinVar VariationId is 259563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000598305.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	NM_004917.5	MANE Select	c.*19C>T		3_prime_UTR	Exon 6 of 6	NP_004908.4
	KLK4	NR_126566.2		n.773C>T		non_coding_transcript_exon	Exon 5 of 5
	KLK4	NM_001302961.2		c.*19C>T		3_prime_UTR	Exon 5 of 5	NP_001289890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000598305.5	TSL:1	n.*279C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000469963.1
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.*19C>T		3_prime_UTR	Exon 6 of 6	ENSP00000326159.1
	KLK4	ENST00000598305.5	TSL:1	n.*279C>T		3_prime_UTR	Exon 5 of 5	ENSP00000469963.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17450 AN: 152038 Hom.: 1152 Cov.: 32

Gnomad AFR AF: 0.0976

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.00924

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.117 AC: 29414 AN: 251472 AF XY: 0.123

Gnomad AFR exome AF: 0.0965

Gnomad AMR exome AF: 0.0681

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.00821

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.132 AC: 192860 AN: 1461190 Hom.: 13552 Cov.: 32 AF XY: 0.134 AC XY: 97175 AN XY: 726980

African (AFR) AF: 0.0999 AC: 3343 AN: 33472

American (AMR) AF: 0.0713 AC: 3187 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2216 AN: 26128

East Asian (EAS) AF: 0.00564 AC: 224 AN: 39696

South Asian (SAS) AF: 0.174 AC: 15012 AN: 86230

European-Finnish (FIN) AF: 0.107 AC: 5722 AN: 53418

Middle Eastern (MID) AF: 0.195 AC: 1123 AN: 5764

European-Non Finnish (NFE) AF: 0.139 AC: 154427 AN: 1111390

Other (OTH) AF: 0.126 AC: 7606 AN: 60374

GnomAD4 genome AF: 0.115 AC: 17444 AN: 152154 Hom.: 1148 Cov.: 32 AF XY: 0.113 AC XY: 8374 AN XY: 74406

African (AFR) AF: 0.0975 AC: 4046 AN: 41512

American (AMR) AF: 0.0855 AC: 1307 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3470

East Asian (EAS) AF: 0.00907 AC: 47 AN: 5180

South Asian (SAS) AF: 0.159 AC: 766 AN: 4812

European-Finnish (FIN) AF: 0.105 AC: 1119 AN: 10610

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9430 AN: 67960

Other (OTH) AF: 0.121 AC: 255 AN: 2112

Alfa AF: 0.120 Hom.: 512

Bravo AF: 0.111

Asia WGS AF: 0.0680 AC: 237 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.47
PhyloP100		-0.11
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: rs73042387; hg19: chr19-51410171;