Variant X-87633908-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.1709A>G(p.Asn570Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000476 in 1,198,374 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 17 hem. )

Consequence

KLHL4
ENST00000373119.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14221856).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL4	NM_019117.5 linkuse as main transcript	c.1709A>G	p.Asn570Ser	missense_variant	8/11	ENST00000373119.9	NP_061990.2
KLHL4	NM_057162.3 linkuse as main transcript	c.1709A>G	p.Asn570Ser	missense_variant	8/11		NP_476503.1
KLHL4	XR_938403.3 linkuse as main transcript	n.1801A>G		non_coding_transcript_exon_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.1709A>G	p.Asn570Ser	missense_variant	8/11	1	NM_019117.5	ENSP00000362211	P1	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.1709A>G	p.Asn570Ser	missense_variant	8/11	1		ENSP00000362206		Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	c.1709A>G	p.Asn570Ser	missense_variant, NMD_transcript_variant	8/12			ENSP00000498718		Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111519

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33687

show subpopulations

Gnomad AFR

AF:

0.0000979

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.0000941

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.0000590

AC:

AN:

169517

Hom.:

AF XY:

0.0000720

AC XY:

AN XY:

55539

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000198

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:

0.0000391

Gnomad OTH exome

AF:

0.000478

GnomAD4 exome

AF:

0.0000405

AC:

AN:

1086855

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

353539

show subpopulations

Gnomad4 AFR exome

AF:

0.0000382

Gnomad4 AMR exome

AF:

0.000235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000193

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000359

Gnomad4 OTH exome

AF:

0.0000657

GnomAD4 genome

AF:

0.000117

AC:

AN:

111519

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33687

show subpopulations

Gnomad4 AFR

AF:

0.0000979

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000941

Gnomad4 OTH

AF:

0.00134

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000742

AC:

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

Dec 30, 2023

The c.1709A>G (p.N570S) alteration is located in exon 8 (coding exon 8) of the KLHL4 gene. This alteration results from a A to G substitution at nucleotide position 1709, causing the asparagine (N) at amino acid position 570 to be replaced by a serine (S). 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

0.066

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.25

T;.

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

0.82

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.59

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.14

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0010

B;B

Vest4

0.13

MVP

0.39

MPC

0.24

ClinPred

0.073

GERP RS

2.0

Varity_R

0.064

gMVP

0.086

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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