rs28730867

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006063.3(KLHL41):c.8C>T(p.Ser3Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,609,052 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 10 hom., cov: 32)

Exomes 𝑓: 0.014 ( 196 hom. )

Consequence

KLHL41
NM_006063.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.57

Publications

12 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=0.006108731).

BP6

Variant 2-169509786-C-T is Benign according to our data. Variant chr2-169509786-C-T is described in ClinVar as Benign. ClinVar VariationId is 259913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00958 (1459/152296) while in subpopulation NFE AF = 0.0156 (1064/68022). AF 95% confidence interval is 0.0149. There are 10 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL41	NM_006063.3 link	c.8C>T	p.Ser3Phe	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.8C>T	p.Ser3Phe	missense_variant	Exon 1 of 6	1	NM_006063.3	ENSP00000284669.1		O60662-1
ENSG00000251569	ENST00000513963.1 link	c.925-4788C>T		intron_variant	Intron 11 of 15	2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.00957

AC:

1457

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00914

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00960

AC:

2370

AN:

246946

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.00555

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00869

Gnomad NFE exome

AF:

0.0149

Gnomad OTH exome

AF:

0.00989

GnomAD4 exome

AF:

0.0143

AC:

20869

AN:

1456756

Hom.:

196

Cov.:

AF XY:

0.0142

AC XY:

10319

AN XY:

724688

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33408

American (AMR)

AF:

0.00537

AC:

239

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00639

AC:

166

AN:

25958

East Asian (EAS)

AF:

0.000126

AC:

AN:

39690

South Asian (SAS)

AF:

0.00707

AC:

608

AN:

85948

European-Finnish (FIN)

AF:

0.00829

AC:

417

AN:

50318

Middle Eastern (MID)

AF:

0.00782

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0168

AC:

18633

AN:

1110864

Other (OTH)

AF:

0.0111

AC:

670

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1046

2091

3137

4182

5228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.00958

AC:

1459

AN:

152296

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

706

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41574

American (AMR)

AF:

0.00719

AC:

110

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00914

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1064

AN:

68022

Other (OTH)

AF:

0.00711

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0141

Hom.:

Bravo

AF:

0.00885

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.0100

AC:

1217

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2019

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 9

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.21

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.1

PhyloP100

7.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.65

REVEL

Benign

0.17

Sift

Benign

0.036

Sift4G

Benign

0.067

Polyphen

0.94

Vest4

0.42

MPC

0.62

ClinPred

0.013

GERP RS

5.0

PromoterAI

0.00050

Neutral

(source)

Varity_R

0.17

gMVP

0.66

Mutation Taster

=89/11

polymorphism

(source)

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

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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