Genetic Variant KLHL33:p.Gly735Arg (chr14-20429040-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001365790.2(KLHL33):c.2203G>A(p.Gly735Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000238 in 1,551,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.94

Publications

1 publications found

Variant links:

Genes affected

KLHL33 (HGNC:31952): (kelch like family member 33)

KLHL33 links:

ENSG00000291038 (HGNC:):

ENSG00000291038 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365790.2. 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
	KLHL33	NM_001365790.2	MANE Select	c.2203G>A	p.Gly735Arg	missense	Exon 5 of 5	NP_001352719.1	A0A1B0GUB7
	KLHL33	NM_001109997.3		c.1411G>A	p.Gly471Arg	missense	Exon 4 of 4	NP_001103467.2	A6NCF5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHL33	ENST00000636854.3	TSL:5 MANE Select	c.2203G>A	p.Gly735Arg	missense	Exon 5 of 5	ENSP00000490040.1	A0A1B0GUB7
KLHL33	ENST00000344581.4	TSL:5	c.1411G>A	p.Gly471Arg	missense	Exon 4 of 4	ENSP00000341549.4	A6NCF5
KLHL33	ENST00000637228.1	TSL:5	c.*362G>A		3_prime_UTR	Exon 4 of 4	ENSP00000489731.1	A0A1B0GTK0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD2 exomes

AF:

0.0000578

AC:

AN:

155684

AF XY:

0.0000485

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000236

AC:

AN:

1399396

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

690200

show subpopulations

African (AFR)

AF:

0.0000949

AC:

AN:

31598

American (AMR)

AF:

0.000168

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000213

AC:

AN:

1078972

Other (OTH)

AF:

0.0000172

AC:

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000724

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

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:

0.0000658

Hom.:

Bravo

AF:

0.0000529

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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.1

PhyloP100

5.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.94

Gain of methylation at G471 (P = 0.0722)

MVP

0.49

ClinPred

0.96

GERP RS

5.4

Varity_R

0.94

gMVP

0.89

Mutation Taster

=37/63

disease causing

(source)

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

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