Variant X-21656166-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_153270.3(KLHL34):c.1623C>G(p.Ile541Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,173,591 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. Variant has been reported in Lovd as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000050 ( 0 hom. 16 hem. )

Consequence

KLHL34
NM_153270.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.182

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-21656166-G-C is Benign according to our data. Variant chrX-21656166-G-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL34	NM_153270.3 linkuse as main transcript	c.1623C>G	p.Ile541Met	missense_variant	1/1	ENST00000379499.3	NP_695002.1	Q8N239

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL34	ENST00000379499.3 linkuse as main transcript	c.1623C>G	p.Ile541Met	missense_variant	1/1	6	NM_153270.3	ENSP00000368813.2		Q8N239

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112019

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34189

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.0000941

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.0000982

AC:

AN:

122206

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

32288

show subpopulations

Gnomad AFR exome

AF:

0.000226

Gnomad AMR exome

AF:

0.000328

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:

0.0000405

Gnomad OTH exome

AF:

0.000305

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1061572

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

340666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000390

Gnomad4 AMR exome

AF:

0.000230

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:

0.0000413

Gnomad4 OTH exome

AF:

0.000179

GnomAD4 genome

AF:

0.0000714

AC:

AN:

112019

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34189

show subpopulations

Gnomad4 AFR

AF:

0.0000650

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:

0.0000941

Gnomad4 OTH

AF:

0.000662

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000257

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

Aug 29, 2024

The c.1623C>G (p.I541M) alteration is located in exon 1 (coding exon 1) of the KLHL34 gene. This alteration results from a C to G substitution at nucleotide position 1623, causing the isoleucine (I) at amino acid position 541 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

0.28

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.45

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.62

MutPred

0.66

Gain of disorder (P = 0.0593);

MVP

0.86

MPC

1.3

ClinPred

0.11

GERP RS

-3.4

Varity_R

0.43

gMVP

0.80

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