Variant 14-20429228-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365790.2(KLHL33):c.2015G>A(p.Arg672Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,551,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.92

Variant links:

Genes affected

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

KLHL33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2 linkuse as main transcript	c.2015G>A	p.Arg672Gln	missense_variant	5/5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	4/4		NP_001103467.2	A6NCF5B2RUZ8
KLHL33	XM_011536450.3 linkuse as main transcript	c.2015G>A	p.Arg672Gln	missense_variant	5/5		XP_011534752.1	A0A1B0GUB7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KLHL33	ENST00000636854.3 linkuse as main transcript	c.2015G>A	p.Arg672Gln	missense_variant	5/5	5	NM_001365790.2	ENSP00000490040.1	A0A1B0GUB7
KLHL33	ENST00000344581.4 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	4/4	5		ENSP00000341549.4	A6NCF5
KLHL33	ENST00000637228 linkuse as main transcript	c.*174G>A		3_prime_UTR_variant	4/4	5		ENSP00000489731.1	A0A1B0GTK0

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000268

AC:

AN:

156656

Hom.:

AF XY:

0.000325

AC XY:

AN XY:

82980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000459

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000824

Gnomad OTH exome

AF:

0.000454

GnomAD4 exome

AF:

0.000111

AC:

156

AN:

1399472

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

690238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.000168

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000476

Gnomad4 SAS exome

AF:

0.000972

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000399

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.000171

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000242

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.1223G>A (p.R408Q) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a G to A substitution at nucleotide position 1223, causing the arginine (R) at amino acid position 408 to be replaced by a glutamine (Q). 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

Uncertain

0.39

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.2

.;H

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.9

.;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.019

.;D

Polyphen

1.0

.;D

Vest4

0.82

MVP

0.39

ClinPred

0.70

GERP RS

5.4

Varity_R

0.77

gMVP

0.69

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

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