NM_004917.5:c.591A>C

Variant names:

• chr19-50908380-T-G
• rs2569527
• NM_004917.5:c.591A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 BS2

The NM_004917.5(KLK4):​c.591A>C​(p.Gln197His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,828 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (28 hom.)
• Consequence: KLK4 NM_004917.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.880
• Publications: 25 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 -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.031208 (below the threshold of 3.09). Trascript score misZ: -0.079907 (below the threshold of 3.09). GenCC associations: The gene is linked to amelogenesis imperfecta type 2, amelogenesis imperfecta type 2A1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03328696).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00306 (466/152240) while in subpopulation NFE AF = 0.0052 (354/68024). AF 95% confidence interval is 0.00476. There are 0 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	NM_004917.5	MANE Select	c.591A>C	p.Gln197His	missense	Exon 5 of 6	NP_004908.4
	KLK4	NM_001302961.2		c.306A>C	p.Gln102His	missense	Exon 4 of 5	NP_001289890.1
	KLK4	NR_126566.2		n.580A>C		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.591A>C	p.Gln197His	missense	Exon 5 of 6	ENSP00000326159.1
	KLK4	ENST00000431178.2	TSL:1	c.328+199A>C		intron	N/A	ENSP00000399448.2
	KLK4	ENST00000596876.1	TSL:1	n.593A>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00423 AC: 6189 AN: 1461588 Hom.: 28 Cov.: 32 AF XY: 0.00429 AC XY: 3121 AN XY: 727106

African (AFR) AF: 0.000627 AC: 21 AN: 33476

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00454 AC: 392 AN: 86252

European-Finnish (FIN) AF: 0.00462 AC: 246 AN: 53224

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5686

European-Non Finnish (NFE) AF: 0.00472 AC: 5248 AN: 1112010

Other (OTH) AF: 0.00388 AC: 234 AN: 60380

GnomAD4 genome AF: 0.00306 AC: 466 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.00316 AC XY: 235 AN XY: 74446

African (AFR) AF: 0.000722 AC: 30 AN: 41538

American (AMR) AF: 0.00196 AC: 30 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00520 AC: 354 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00363 Hom.: 4

Bravo AF: 0.00244

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_noAF	Benign	-0.97
CADD	Benign	8.0
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.033	T
PhyloP100		-0.88
Sift4G	Uncertain	0.033	D
Vest4		0.16
gMVP		0.35

Splicing

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

Other links and lift over

dbSNP: rs2569527; hg19: chr19-51411636;