Variant X-21656869-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_153270.3(KLHL34):c.920G>C(p.Gly307Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,176,074 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. 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 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 9 hem. )

Consequence

KLHL34
NM_153270.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.244

Variant links:

Genes affected

KLHL34 (HGNC:26634): (kelch like family member 34) Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

KLHL34 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034243613).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL34	NM_153270.3 linkuse as main transcript	c.920G>C	p.Gly307Ala	missense_variant	1/1	ENST00000379499.3	NP_695002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL34	ENST00000379499.3 linkuse as main transcript	c.920G>C	p.Gly307Ala	missense_variant	1/1		NM_153270.3	ENSP00000368813	P1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112375

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34537

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:

0.000564

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

GnomAD3 exomes

AF:

0.0000744

AC:

AN:

134391

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

36553

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000818

Gnomad SAS 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:

0.0000160

AC:

AN:

1063699

Hom.:

Cov.:

AF XY:

0.0000265

AC XY:

AN XY:

340223

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000469

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000672

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112375

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34537

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000564

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000336

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.920G>C (p.G307A) alteration is located in exon 1 (coding exon 1) of the KLHL34 gene. This alteration results from a G to C substitution at nucleotide position 920, causing the glycine (G) at amino acid position 307 to be replaced by an alanine (A). 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

0.095

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.4

DANN

Benign

0.71

DEOGEN2

Benign

0.021

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.52

M_CAP

Benign

0.025

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.97

REVEL

Benign

0.053

Sift

Benign

0.18

Sift4G

Uncertain

0.026

Polyphen

0.18

Vest4

0.10

MutPred

0.28

Gain of relative solvent accessibility (P = 0.0249);

MVP

0.91

MPC

0.47

ClinPred

0.025

GERP RS

3.8

Varity_R

0.070

gMVP

0.26

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