rs147294651

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006063.3(KLHL41):c.398G>A(p.Gly133Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,058 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 24 hom. )

Consequence

KLHL41
NM_006063.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.93

Variant links:

Genes affected

KLHL41 (HGNC:16905): (kelch like family member 41) This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]

KLHL41 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012224913).

BP6

Variant 2-169510176-G-A is Benign according to our data. Variant chr2-169510176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00139 (212/152196) while in subpopulation SAS AF= 0.00872 (42/4816). AF 95% confidence interval is 0.00663. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL41	NM_006063.3 linkuse as main transcript	c.398G>A	p.Gly133Asp	missense_variant	1/6	ENST00000284669.2	NP_006054.2	O60662-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2 linkuse as main transcript	c.398G>A	p.Gly133Asp	missense_variant	1/6	1	NM_006063.3	ENSP00000284669.1		O60662-1
ENSG00000251569	ENST00000513963.1 linkuse as main transcript	c.925-4398G>A		intron_variant		2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00224

AC:

561

AN:

250590

Hom.:

AF XY:

0.00267

AC XY:

362

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0000636

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00810

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

AF:

0.00179

AC:

2617

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1469

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00837

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.00222

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152196

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00872

Gnomad4 FIN

AF:

0.000567

Gnomad4 NFE

AF:

0.00185

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00220

AC:

267

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KLHL41: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	- -

KLHL41-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.031

Eigen

Benign

0.040

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.12

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.5

REVEL

Benign

0.11

Sift

Benign

0.33

Sift4G

Uncertain

0.049

Polyphen

0.57

Vest4

0.54

MVP

0.77

MPC

0.52

ClinPred

0.023

GERP RS

4.3

Varity_R

0.13

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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