Variant 14-20429511-T-G 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.1832A>C(p.Asn611Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,552,108 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N611S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KLHL33
NM_001365790.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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
KLHL33	NM_001365790.2 linkuse as main transcript	c.1832A>C	p.Asn611Thr	missense_variant	4/5	ENST00000636854.3
KLHL33	NM_001109997.3 linkuse as main transcript	c.1040A>C	p.Asn347Thr	missense_variant	3/4
KLHL33	XM_011536450.3 linkuse as main transcript	c.1832A>C	p.Asn611Thr	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KLHL33	ENST00000636854.3 linkuse as main transcript	c.1832A>C	p.Asn611Thr	missense_variant	4/5	5	NM_001365790.2	P1
KLHL33	ENST00000637228.1 linkuse as main transcript	c.1832A>C	p.Asn611Thr	missense_variant	3/4	5
KLHL33	ENST00000344581.4 linkuse as main transcript	c.1040A>C	p.Asn347Thr	missense_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000252

AC:

AN:

158596

Hom.:

AF XY:

0.0000359

AC XY:

AN XY:

83492

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:

0.0000586

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1400008

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

690472

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000202

Gnomad4 NFE exome

AF:

0.0000222

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

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

Jun 22, 2023

The c.1040A>C (p.N347T) alteration is located in exon 3 (coding exon 2) of the KLHL33 gene. This alteration results from a A to C substitution at nucleotide position 1040, causing the asparagine (N) at amino acid position 347 to be replaced by a threonine (T). 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

0.47

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

0.21

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

Polyphen

0.95

.;.;P

Vest4

0.27

MVP

0.29

ClinPred

0.79

GERP RS

5.3

Varity_R

0.76

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