Genetic Variant NM_019117.5:c.1501A>G (chrX-87632386-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -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

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18596628).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019117.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL4	NM_019117.5	MANE Select	c.1501A>G	p.Lys501Glu	missense	Exon 7 of 11	NP_061990.2
	KLHL4	NM_057162.3		c.1501A>G	p.Lys501Glu	missense	Exon 7 of 11	NP_476503.1	Q9C0H6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHL4	ENST00000373119.9	TSL:1 MANE Select	c.1501A>G	p.Lys501Glu	missense	Exon 7 of 11	ENSP00000362211.4	Q9C0H6-1
KLHL4	ENST00000373114.4	TSL:1	c.1501A>G	p.Lys501Glu	missense	Exon 7 of 11	ENSP00000362206.4	Q9C0H6-2
KLHL4	ENST00000858463.1		c.1501A>G	p.Lys501Glu	missense	Exon 7 of 11	ENSP00000528522.1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111901

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000328

AC:

AN:

182820

AF XY:

0.0000148

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 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

African (AFR)

AF:

0.00

AC:

AN:

26381

American (AMR)

AF:

0.00

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30185

South Asian (SAS)

AF:

0.00

AC:

AN:

54064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840822

Other (OTH)

AF:

0.000282

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000357

AC:

AN:

111901

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34065

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30767

American (AMR)

AF:

0.00

AC:

AN:

10471

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00113

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6033

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53297

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.065

PhyloP100

6.9

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.32

Sift

Benign

0.12

Sift4G

Benign

0.15

Polyphen

0.18

Vest4

0.46

MutPred

0.54

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

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over