Variant 14-20428964-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001365790.2(KLHL33):c.2279G>T(p.Cys760Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,551,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.700

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22511783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL33	NM_001365790.2 linkuse as main transcript	c.2279G>T	p.Cys760Phe	missense_variant	5/5	ENST00000636854.3	NP_001352719.1
KLHL33	NM_001109997.3 linkuse as main transcript	c.1487G>T	p.Cys496Phe	missense_variant	4/4		NP_001103467.2	A6NCF5B2RUZ8
KLHL33	XM_011536450.3 linkuse as main transcript	c.2279G>T	p.Cys760Phe	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.2279G>T	p.Cys760Phe	missense_variant	5/5	5	NM_001365790.2	ENSP00000490040.1	A0A1B0GUB7
KLHL33	ENST00000344581.4 linkuse as main transcript	c.1487G>T	p.Cys496Phe	missense_variant	4/4	5		ENSP00000341549.4	A6NCF5
KLHL33	ENST00000637228 linkuse as main transcript	c.*438G>T		3_prime_UTR_variant	4/4	5		ENSP00000489731.1	A0A1B0GTK0

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

156296

Hom.:

AF XY:

0.0000362

AC XY:

AN XY:

82854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000827

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000219

AC:

307

AN:

1399414

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

149

AN XY:

690214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000280

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

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

May 31, 2023

The c.1487G>T (p.C496F) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a G to T substitution at nucleotide position 1487, causing the cysteine (C) at amino acid position 496 to be replaced by a phenylalanine (F). 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

Benign

0.29

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

.;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.19

Sift

Benign

0.031

.;D

Sift4G

Uncertain

0.026

.;D

Polyphen

0.99

.;D

Vest4

0.25

MutPred

0.44

.;Loss of catalytic residue at L497 (P = 0.1014);

MVP

0.27

ClinPred

0.24

GERP RS

4.3

Varity_R

0.22

gMVP

0.42

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