Variant X-87625694-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_019117.5(KLHL4):c.1222C>A(p.Leu408Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000034 in 1,207,225 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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 0.00013 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000025 ( 0 hom. 9 hem. )

Consequence

KLHL4
NM_019117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41463545).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL4	NM_019117.5 linkuse as main transcript	c.1222C>A	p.Leu408Ile	missense_variant	6/11	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 linkuse as main transcript	c.1222C>A	p.Leu408Ile	missense_variant	6/11		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 linkuse as main transcript	n.1314C>A		non_coding_transcript_exon_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 linkuse as main transcript	c.1222C>A	p.Leu408Ile	missense_variant	6/11	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 linkuse as main transcript	c.1222C>A	p.Leu408Ile	missense_variant	6/11	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 linkuse as main transcript	n.1222C>A		non_coding_transcript_exon_variant	6/12			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111671

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33833

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

181806

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

66454

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.000185

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:

0.00

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1095554

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000484

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:

0.00000238

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000125

AC:

AN:

111671

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

33833

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000317

ExAC

AF:

0.0000165

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 22, 2023

The c.1222C>A (p.L408I) alteration is located in exon 6 (coding exon 6) of the KLHL4 gene. This alteration results from a C to A substitution at nucleotide position 1222, causing the leucine (L) at amino acid position 408 to be replaced by an isoleucine (I). 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

Uncertain

0.56

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.53

MutPred

0.51

Loss of disorder (P = 0.0567);Loss of disorder (P = 0.0567);

MVP

0.75

MPC

1.0

ClinPred

0.46

GERP RS

4.9

Varity_R

0.77

gMVP

0.31

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