Genetic Variant KLHL33:p.Val612Ala (chr14-20429508-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365790.2(KLHL33):c.1835T>C(p.Val612Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,552,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V612I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15010071).

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.1835T>C	p.Val612Ala	missense	Exon 4 of 5	NP_001352719.1	A0A1B0GUB7
	KLHL33	NM_001109997.3		c.1043T>C	p.Val348Ala	missense	Exon 3 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.1835T>C	p.Val612Ala	missense	Exon 4 of 5	ENSP00000490040.1	A0A1B0GUB7
KLHL33	ENST00000637228.1	TSL:5	c.1835T>C	p.Val612Ala	missense	Exon 3 of 4	ENSP00000489731.1	A0A1B0GTK0
KLHL33	ENST00000344581.4	TSL:5	c.1043T>C	p.Val348Ala	missense	Exon 3 of 4	ENSP00000341549.4	A6NCF5

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

158572

AF XY:

0.0000120

show subpopulations

Gnomad AFR exome

AF:

0.000240

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1400016

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690472

show subpopulations

African (AFR)

AF:

0.000380

AC:

AN:

31600

American (AMR)

AF:

0.0000560

AC:

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079102

Other (OTH)

AF:

0.00

AC:

AN:

58194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000105

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000165

Hom.:

Bravo

AF:

0.000159

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

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.31

M_CAP

Benign

0.017

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.28

PhyloP100

1.1

PrimateAI

Benign

0.34

PROVEAN

Benign

0.79

REVEL

Benign

0.13

Sift

Benign

0.74

Sift4G

Benign

0.81

Polyphen

0.0010

Vest4

0.069

MVP

0.092

ClinPred

0.032

GERP RS

3.0

Varity_R

0.036

gMVP

0.27

Mutation Taster

=92/8

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

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