Genetic Variant KLHL33:p.Arg740His (chr14-20429024-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365790.2(KLHL33):c.2219G>A(p.Arg740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000741 in 1,551,734 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 2 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.09

Publications

3 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00581643).

BP6

Variant 14-20429024-C-T is Benign according to our data. Variant chr14-20429024-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2644049.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.2219G>A	p.Arg740His	missense	Exon 5 of 5	NP_001352719.1	A0A1B0GUB7
	KLHL33	NM_001109997.3		c.1427G>A	p.Arg476His	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.2219G>A	p.Arg740His	missense	Exon 5 of 5	ENSP00000490040.1	A0A1B0GUB7
KLHL33	ENST00000344581.4	TSL:5	c.1427G>A	p.Arg476His	missense	Exon 4 of 4	ENSP00000341549.4	A6NCF5
KLHL33	ENST00000637228.1	TSL:5	c.*378G>A		3_prime_UTR	Exon 4 of 4	ENSP00000489731.1	A0A1B0GTK0

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00851

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.000854

AC:

133

AN:

155668

AF XY:

0.000727

show subpopulations

Gnomad AFR exome

AF:

0.00897

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.000472

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.000915

GnomAD4 exome

AF:

0.000525

AC:

734

AN:

1399388

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

350

AN XY:

690200

show subpopulations

African (AFR)

AF:

0.00997

AC:

315

AN:

31598

American (AMR)

AF:

0.00123

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.000477

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.000126

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000252

AC:

272

AN:

1078972

Other (OTH)

AF:

0.00121

AC:

AN:

58006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00273

AC:

416

AN:

152346

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

194

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00851

AC:

354

AN:

41582

American (AMR)

AF:

0.00176

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68022

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00326

ESP6500AA

AF:

0.0130

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.00106

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.010

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.52

REVEL

Benign

0.056

Sift

Benign

0.064

Sift4G

Benign

0.12

Polyphen

0.85

Vest4

0.084

MVP

0.081

ClinPred

0.0080

GERP RS

1.3

Varity_R

0.031

gMVP

0.39

Mutation Taster

=98/2

polymorphism

(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

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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