Genetic Variant NM_004917.5:c.61+144C>A (chr19-50910534-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004917.5(KLK4):c.61+144C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 623,734 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KLK4
NM_004917.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

Publications

0 publications found

Variant links:

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

KLK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5 link	c.61+144C>A	intron_variant	Intron 2 of 5	ENST00000324041.6	NP_004908.4	Q9Y5K2A0A0C4DFQ5
KLK4	NM_001302961.2 link	c.-237+144C>A	intron_variant	Intron 1 of 4		NP_001289890.1	Q9Y5K2Q5BQA0
KLK4	NR_126566.2 link	n.61+144C>A	intron_variant	Intron 1 of 4
KLK4	XM_011527545.4 link	c.61+144C>A	intron_variant	Intron 1 of 3		XP_011525847.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLK4	ENST00000324041.6 link	c.61+144C>A	intron_variant	Intron 2 of 5	1	NM_004917.5	ENSP00000326159.1	A0A0C4DFQ5
KLK4	ENST00000598305.5 link	n.-218+144C>A	intron_variant	Intron 1 of 4	1		ENSP00000469963.1	M0QYN5
KLK4	ENST00000602148.1 link	n.61+144C>A	intron_variant	Intron 1 of 4	1		ENSP00000472091.1	Q5BQA0

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151960

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000160

AC:

AN:

623734

Hom.:

AF XY:

0.00

AC XY:

AN XY:

332148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16810

American (AMR)

AF:

0.00

AC:

AN:

34546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20166

East Asian (EAS)

AF:

0.0000312

AC:

AN:

32048

South Asian (SAS)

AF:

0.00

AC:

AN:

63228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

375558

Other (OTH)

AF:

0.00

AC:

AN:

32548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74190

African (AFR)

AF:

0.00

AC:

AN:

41324

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2086

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

8.4

(source)

DANN

Benign

0.45

PhyloP100

1.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over