rs198965

Variant names:

• chr19-50907142-G-A
• rs198965
• NM_004917.5:c.613-56C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50907142-G-A
• chr19-50907142-G-T

Variant summary

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

The NM_004917.5(KLK4):​c.613-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,577,026 control chromosomes in the GnomAD database, including 1,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (124 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1064 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.352
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-50907142-G-A is Benign according to our data. Variant chr19-50907142-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0679 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.613-56C>T		intron	N/A	NP_004908.4
	KLK4	NM_001302961.2		c.328-56C>T		intron	N/A	NP_001289890.1
	KLK4	NR_126566.2		n.602-56C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.613-56C>T		intron	N/A	ENSP00000326159.1	A0A0C4DFQ5
	KLK4	ENST00000431178.2	TSL:1	c.329-56C>T		intron	N/A	ENSP00000399448.2	Q9Y5K2-2
	KLK4	ENST00000598305.5	TSL:1	n.*108-56C>T		intron	N/A	ENSP00000469963.1	M0QYN5

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4643 AN: 152168 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00746

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.0347 AC: 49469 AN: 1424740 Hom.: 1064 AF XY: 0.0339 AC XY: 24078 AN XY: 711004

African (AFR) AF: 0.00581 AC: 190 AN: 32686

American (AMR) AF: 0.0956 AC: 4256 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 1061 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.0213 AC: 1822 AN: 85394

European-Finnish (FIN) AF: 0.0558 AC: 2968 AN: 53206

Middle Eastern (MID) AF: 0.00926 AC: 45 AN: 4862

European-Non Finnish (NFE) AF: 0.0346 AC: 37316 AN: 1079682

Other (OTH) AF: 0.0307 AC: 1811 AN: 58986

GnomAD4 genome AF: 0.0305 AC: 4648 AN: 152286 Hom.: 124 Cov.: 32 AF XY: 0.0328 AC XY: 2439 AN XY: 74470

African (AFR) AF: 0.00743 AC: 309 AN: 41564

American (AMR) AF: 0.0714 AC: 1092 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4826

European-Finnish (FIN) AF: 0.0660 AC: 700 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2207 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0143 Hom.: 4

Bravo AF: 0.0300

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.18
PhyloP100		-0.35
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: rs198965; hg19: chr19-51410398;