dbSNP rs767979837: KLHL4:p.Lys501Glu (chrX-87632386-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_019117.5(KLHL4):c.1501A>G(p.Lys501Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,208,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

KLHL4
NM_019117.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.93

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=0.18596628).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL4	NM_019117.5 link	c.1501A>G	p.Lys501Glu	missense_variant	Exon 7 of 11	ENST00000373119.9	NP_061990.2	Q9C0H6-1A5PKX1
KLHL4	NM_057162.3 link	c.1501A>G	p.Lys501Glu	missense_variant	Exon 7 of 11		NP_476503.1	Q9C0H6-2
KLHL4	XR_938403.3 link	n.1593A>G		non_coding_transcript_exon_variant	Exon 7 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL4	ENST00000373119.9 link	c.1501A>G	p.Lys501Glu	missense_variant	Exon 7 of 11	1	NM_019117.5	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4 link	c.1501A>G	p.Lys501Glu	missense_variant	Exon 7 of 11	1		ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000652270.1 link	n.1501A>G		non_coding_transcript_exon_variant	Exon 7 of 12			ENSP00000498718.1	Q9C0H6-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111901

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34065

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00113

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:

0.0000328

AC:

AN:

182820

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad SAS exome

AF:

0.0000527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1096726

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.0000357

AC:

AN:

111901

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34065

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00113

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

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

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1501A>G (p.K501E) alteration is located in exon 7 (coding exon 7) of the KLHL4 gene. This alteration results from a A to G substitution at nucleotide position 1501, causing the lysine (K) at amino acid position 501 to be replaced by a glutamic acid (E). 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

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.065

N;N

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.12

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.18

B;B

Vest4

0.46

MutPred

0.54

Loss of methylation at K501 (P = 0.0011);Loss of methylation at K501 (P = 0.0011);

MVP

0.46

MPC

0.56

ClinPred

0.24

GERP RS

5.3

Varity_R

0.43

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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