rs28763868

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006063.3(KLHL41):c.811G>A(p.Ala271Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,940 control chromosomes in the GnomAD database, including 8,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A271V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.081 ( 639 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8213 hom. )

Consequence

KLHL41
NM_006063.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.02

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

nemaline myopathy 9
Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
childhood-onset nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intermediate nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
typical nemaline myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLHL41 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016920269).

BP6

Variant 2-169510589-G-A is Benign according to our data. Variant chr2-169510589-G-A is described in ClinVar as Benign. ClinVar VariationId is 259911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL41	NM_006063.3 link	c.811G>A	p.Ala271Thr	missense_variant	Exon 1 of 6	ENST00000284669.2	NP_006054.2	O60662-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2 link	c.811G>A	p.Ala271Thr	missense_variant	Exon 1 of 6	1	NM_006063.3	ENSP00000284669.1		O60662-1
ENSG00000251569	ENST00000513963.1 link	c.925-3985G>A		intron_variant	Intron 11 of 15	2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.0810

AC:

12315

AN:

152026

Hom.:

640

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.0664

Gnomad ASJ

AF:

0.0686

Gnomad EAS

AF:

0.0142

Gnomad SAS

AF:

0.0831

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.113

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0857

AC:

21553

AN:

251440

AF XY:

0.0882

show subpopulations

Gnomad AFR exome

AF:

0.0386

Gnomad AMR exome

AF:

0.0485

Gnomad ASJ exome

AF:

0.0712

Gnomad EAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.0911

GnomAD4 exome

AF:

0.102

AC:

149111

AN:

1461796

Hom.:

8213

Cov.:

AF XY:

0.101

AC XY:

73802

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0344

AC:

1153

AN:

33478

American (AMR)

AF:

0.0507

AC:

2266

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0750

AC:

1961

AN:

26136

East Asian (EAS)

AF:

0.00786

AC:

312

AN:

39700

South Asian (SAS)

AF:

0.0763

AC:

6582

AN:

86252

European-Finnish (FIN)

AF:

0.108

AC:

5780

AN:

53420

Middle Eastern (MID)

AF:

0.0671

AC:

387

AN:

5768

European-Non Finnish (NFE)

AF:

0.113

AC:

125173

AN:

1111926

Other (OTH)

AF:

0.0910

AC:

5497

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7630

15260

22891

30521

38151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4414

8828

13242

17656

22070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0809

AC:

12310

AN:

152144

Hom.:

639

Cov.:

AF XY:

0.0805

AC XY:

5985

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0356

AC:

1477

AN:

41518

American (AMR)

AF:

0.0663

AC:

1014

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0686

AC:

238

AN:

3468

East Asian (EAS)

AF:

0.0143

AC:

AN:

5182

South Asian (SAS)

AF:

0.0832

AC:

400

AN:

4810

European-Finnish (FIN)

AF:

0.108

AC:

1143

AN:

10566

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.113

AC:

7698

AN:

67992

Other (OTH)

AF:

0.0762

AC:

161

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

589

1178

1768

2357

2946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0994

Hom.:

3387

Bravo

AF:

0.0753

TwinsUK

AF:

0.116

AC:

429

ALSPAC

AF:

0.115

AC:

443

ESP6500AA

AF:

0.0420

AC:

185

ESP6500EA

AF:

0.112

AC:

959

ExAC

AF:

0.0874

AC:

10613

Asia WGS

AF:

0.0690

AC:

240

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nemaline myopathy 9

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.66

REVEL

Benign

0.15

Sift

Benign

0.51

Sift4G

Benign

0.55

Polyphen

0.0030

Vest4

0.044

MPC

0.29

ClinPred

0.0091

GERP RS

2.6

Varity_R

0.032

gMVP

0.35

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over