15-74615813-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000345005.8(CLK3):c.1-3384T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CLK3 ENST00000345005.8 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.529

Genes affected

CLK3 (HGNC:2071): (CDC like kinase 3) This gene encodes a protein belonging to the serine/threonine type protein kinase family. This protein is a nuclear dual-specificity kinase that regulates the intranuclear distribution of the serine/arginine-rich (SR) family of splicing factors. Two transcript variants encoding different isoforms have been found for this gene. Related pseudogenes are located on chromosomes 1 and 9. [provided by RefSeq, Jul 2008]

LOC102723750 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079503536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLK3	NM_003992.5	c.1-3384T>A		intron_variant
CLK3	NM_001130028.2			upstream_gene_variant		ENST00000395066.9
LOC102723750	XR_007064714.1			upstream_gene_variant
LOC102723750	XR_007064715.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLK3	ENST00000395066.9			upstream_gene_variant		1	NM_001130028.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094024 Hom.: 0 Cov.: 31 AF XY: 0.00000193 AC XY: 1 AN XY: 519156

Gnomad4 AFR exome AF: 0.0000431

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.359T>A (p.L120Q) alteration is located in exon 1 (coding exon 1) of the CLK3 gene. This alteration results from a T to A substitution at nucleotide position 359, causing the leucine (L) at amino acid position 120 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.71
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.060	N
Sift	Benign	0.057	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.013	B
Vest4		0.096
MutPred		0.19		Loss of methylation at R115 (P = 0.0812);
MVP		0.29
MPC		0.17
ClinPred		0.086	T
GERP RS		0.55
Varity_R		0.10
gMVP		0.13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74908154;