19-50860405-G-T

Variant names:

• chr19-50860405-G-T
• rs6998
• ENST00000422986.6:n.*720G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000422986.6(KLK3):​n.*720G>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 0.0000208 in 144,188 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: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KLK3 ENST00000422986.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.711
• Publications: 16 publications found

Genes affected

KLK3 (HGNC:6364): (kallikrein related peptidase 3) 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. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

ACMG classification

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=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000422986.6. 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
	KLK3	NM_001648.2	MANE Select	c.*278G>T		3_prime_UTR	Exon 5 of 5	NP_001639.1
	KLK3	NM_001030047.1		c.*789G>T		3_prime_UTR	Exon 5 of 5	NP_001025218.1
	KLK3	NM_001030048.1		c.*278G>T		3_prime_UTR	Exon 5 of 5	NP_001025219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK3	ENST00000422986.6	TSL:1	n.*720G>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000393628.2
	KLK3	ENST00000596333.1	TSL:1	n.1242G>T		non_coding_transcript_exon	Exon 4 of 4
	KLK3	ENST00000601349.5	TSL:1	n.2343G>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000208 AC: 3 AN: 144188 Hom.: 0 Cov.: 0 AF XY: 0.0000270 AC XY: 2 AN XY: 74188

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

African (AFR) AF: 0.00 AC: 0 AN: 5332

American (AMR) AF: 0.00 AC: 0 AN: 5946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5156

East Asian (EAS) AF: 0.00 AC: 0 AN: 10374

South Asian (SAS) AF: 0.000119 AC: 1 AN: 8416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 712

European-Non Finnish (NFE) AF: 0.0000222 AC: 2 AN: 89922

Other (OTH) AF: 0.00 AC: 0 AN: 9220

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.65
PhyloP100		-0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6998; hg19: chr19-51363661;