Variant 15-85768045-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022480.4(KLHL25):c.1766C>T(p.Ala589Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,609,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

KLHL25
NM_022480.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

KLHL25 (HGNC:25732): (kelch like family member 25) Involved in protein ubiquitination; regulation of translational initiation; and ubiquitin-dependent protein catabolic process. Located in cytoplasm. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KLHL25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04777205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KLHL25	NM_022480.4 linkuse as main transcript	c.1766C>T	p.Ala589Val	missense_variant	2/3	ENST00000337975.6
KLHL25	XM_047432937.1 linkuse as main transcript	c.1766C>T	p.Ala589Val	missense_variant	2/3
KLHL25	XM_047432938.1 linkuse as main transcript	c.1766C>T	p.Ala589Val	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL25	ENST00000337975.6 linkuse as main transcript	c.1766C>T	p.Ala589Val	missense_variant	2/3	1	NM_022480.4	P1
KLHL25	ENST00000559131.1 linkuse as main transcript	n.154-7034C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000201

AC:

AN:

248618

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

134390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00127

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000274

AC:

399

AN:

1456812

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

180

AN XY:

723686

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00113

Gnomad4 NFE exome

AF:

0.000280

Gnomad4 OTH exome

AF:

0.000333

GnomAD4 genome

AF:

0.000171

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2023

The c.1766C>T (p.A589V) alteration is located in exon 2 (coding exon 1) of the KLHL25 gene. This alteration results from a C to T substitution at nucleotide position 1766, causing the alanine (A) at amino acid position 589 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.015

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.034

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.64

REVEL

Benign

0.29

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

0.93

Vest4

0.36

MVP

0.66

MPC

0.15

ClinPred

0.20

GERP RS

5.7

Varity_R

0.084

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over