Variant 14-20428953-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001365790.2(KLHL33):c.2290C>A(p.Leu764Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000679 in 1,551,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.401

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044234872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KLHL33	NM_001365790.2 linkuse as main transcript	c.2290C>A	p.Leu764Met	missense_variant	5/5	ENST00000636854.3
KLHL33	NM_001109997.3 linkuse as main transcript	c.1498C>A	p.Leu500Met	missense_variant	4/4
KLHL33	XM_011536450.3 linkuse as main transcript	c.2290C>A	p.Leu764Met	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KLHL33	ENST00000636854.3 linkuse as main transcript	c.2290C>A	p.Leu764Met	missense_variant	5/5	5	NM_001365790.2	P1
KLHL33	ENST00000344581.4 linkuse as main transcript	c.1498C>A	p.Leu500Met	missense_variant	4/4	5
KLHL33	ENST00000637228.1 linkuse as main transcript	c.*449C>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000486

AC:

AN:

156352

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

82878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000729

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:

0.000909

Gnomad OTH exome

AF:

0.000683

GnomAD4 exome

AF:

0.000703

AC:

984

AN:

1399404

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

479

AN XY:

690218

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000842

Gnomad4 OTH exome

AF:

0.000603

GnomAD4 genome

AF:

0.000453

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000768

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

Sep 15, 2021

The c.1498C>A (p.L500M) alteration is located in exon 4 (coding exon 3) of the KLHL33 gene. This alteration results from a C to A substitution at nucleotide position 1498, causing the leucine (L) at amino acid position 500 to be replaced by a methionine (M). 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

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.026

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.56

Polyphen

0.79

.;P

Vest4

0.29

MVP

0.040

ClinPred

0.091

GERP RS

3.2

Varity_R

0.36

gMVP

0.46

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