Variant X-87635573-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 NM_019117.5(KLHL4):c.1723A>G(p.Ile575Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,204,681 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000029 ( 0 hom. 14 hem. )

Consequence

KLHL4
NM_019117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

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:

KLHL4 (HGNC:):

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=0.112976074).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5 linkuse as main transcript	c.1723A>G	p.Ile575Val	missense_variant	9/11	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 linkuse as main transcript	c.1723A>G	p.Ile575Val	missense_variant	9/11		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 linkuse as main transcript	n.1815A>G		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.1723A>G	p.Ile575Val	missense_variant	9/11	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.1723A>G	p.Ile575Val	missense_variant	9/11	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	n.1723A>G		non_coding_transcript_exon_variant	9/12			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111881

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34067

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000330

AC:

AN:

181749

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

66453

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000618

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1092800

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

358474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000358

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111881

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34067

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

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

Mar 03, 2022

The c.1723A>G (p.I575V) alteration is located in exon 9 (coding exon 9) of the KLHL4 gene. This alteration results from a A to G substitution at nucleotide position 1723, causing the isoleucine (I) at amino acid position 575 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

0.052

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.18

T;.

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.17

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.59

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.18

MVP

0.26

MPC

0.24

ClinPred

0.10

GERP RS

0.83

Varity_R

0.048

gMVP

0.30

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