Variant X-87518015-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000373119.9(KLHL4):c.122A>G(p.Tyr41Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,209,622 control chromosomes in the GnomAD database, including 1 homozygotes. There are 196 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00054 ( 1 hom. 188 hem. )

Consequence

KLHL4
ENST00000373119.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

KLHL4 (HGNC:6355): (kelch like family member 4) This gene encodes a member of the kelch family of proteins, which are characterized by kelch repeat motifs and a POZ/BTB protein-binding domain. It is thought that kelch repeats are actin binding domains. However, the specific function of this protein has not been determined. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

KLHL4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10048732).

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL4	NM_019117.5 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	1/11	ENST00000373119.9	NP_061990.2
KLHL4	NM_057162.3 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	1/11		NP_476503.1
KLHL4	XR_938403.3 linkuse as main transcript	n.214A>G		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	1/11	1	NM_019117.5	ENSP00000362211	P1	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant	1/11	1		ENSP00000362206		Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	c.122A>G	p.Tyr41Cys	missense_variant, NMD_transcript_variant	1/12			ENSP00000498718		Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.000323

AC:

AN:

111482

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

33642

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000621

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000300

AC:

AN:

183265

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

67747

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000636

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000541

AC:

594

AN:

1098140

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

188

AN XY:

363522

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

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:

0.0000493

Gnomad4 NFE exome

AF:

0.000688

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000323

AC:

AN:

111482

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

33642

show subpopulations

Gnomad4 AFR

AF:

0.0000977

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000621

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000744

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000764

EpiControl

AF:

0.000356

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

Sep 06, 2022

The c.122A>G (p.Y41C) alteration is located in exon 1 (coding exon 1) of the KLHL4 gene. This alteration results from a A to G substitution at nucleotide position 122, causing the tyrosine (Y) at amino acid position 41 to be replaced by a cysteine (C). 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

0.078

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

T;.

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.85

T;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.62

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.082

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0030

B;B

Vest4

0.39

MVP

0.90

MPC

0.35

ClinPred

0.016

GERP RS

3.9

Varity_R

0.16

gMVP

0.32

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