rs138791086

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152393.4(KLHL40):c.1273G>A(p.Gly425Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,998 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G425G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 2.88

Publications

4 publications found

Variant links:

Genes affected

KLHL40 (HGNC:30372): (kelch like family member 40) This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

KLHL40 Gene-Disease associations (from GenCC):

nemaline myopathy 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLHL40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01951465).

BP6

Variant 3-42688262-G-A is Benign according to our data. Variant chr3-42688262-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474324.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00116 (1693/1461810) while in subpopulation EAS AF = 0.00456 (181/39700). AF 95% confidence interval is 0.00402. There are 4 homozygotes in GnomAdExome4. There are 835 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152393.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1273G>A	p.Gly425Ser	missense	Exon 2 of 6	NP_689606.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1273G>A	p.Gly425Ser	missense	Exon 2 of 6	ENSP00000287777.4	Q2TBA0-1
KLHL40	ENST00000942348.1		c.1273G>A	p.Gly425Ser	missense	Exon 2 of 6	ENSP00000612407.1
KLHL40	ENST00000942349.1		c.1273G>A	p.Gly425Ser	missense	Exon 2 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes

AF:

0.000809

AC:

123

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000963

AC:

242

AN:

251234

AF XY:

0.000957

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00116

AC:

1693

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

835

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00456

AC:

181

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00124

AC:

1380

AN:

1112004

Other (OTH)

AF:

0.000745

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000808

AC:

123

AN:

152188

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41522

American (AMR)

AF:

0.000850

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000775

AC:

AN:

5164

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

68012

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00125

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 8 (3)

not provided (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.6

PhyloP100

2.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.2

REVEL

Benign

0.093

Sift

Benign

0.37

Sift4G

Benign

0.64

Polyphen

0.11

Vest4

0.27

MVP

0.78

MPC

0.068

ClinPred

0.021

GERP RS

3.1

Varity_R

0.13

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over