rs28730867

Variant summary

Our verdict is Benign. Variant got -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:3

Conservation

PhyloP100: 7.57

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:

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=0.006108731).

BP6

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

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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL41	NM_006063.3 linkuse as main transcript	c.8C>T	p.Ser3Phe	missense_variant	1/6	ENST00000284669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL41	ENST00000284669.2 linkuse as main transcript	c.8C>T	p.Ser3Phe	missense_variant	1/6	1	NM_006063.3	P1	O60662-1

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

GnomAD3 exomes

AF:

0.00960

AC:

2370

AN:

246946

Hom.:

AF XY:

0.0101

AC XY:

1345

AN XY:

133764

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 SAS exome

AF:

0.00704

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

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.00537

Gnomad4 ASJ exome

AF:

0.00639

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00707

Gnomad4 FIN exome

AF:

0.00829

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00958

AC:

1459

AN:

152296

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

706

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00719

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.00914

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.0145

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2019

- -

Nemaline myopathy 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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

MutationTaster

Benign

1.0

D;D

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

Varity_R

0.17

gMVP

0.66

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