dbSNP rs142285083: KLHL40:p.Arg138Pro (chr3-42686031-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_152393.4(KLHL40):c.413G>C(p.Arg138Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,608,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.98

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

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.413G>C	p.Arg138Pro	missense	Exon 1 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.413G>C	p.Arg138Pro	missense	Exon 1 of 6	ENSP00000287777.4	Q2TBA0-1
KLHL40	ENST00000942348.1		c.413G>C	p.Arg138Pro	missense	Exon 1 of 6	ENSP00000612407.1
KLHL40	ENST00000942349.1		c.413G>C	p.Arg138Pro	missense	Exon 1 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000106

AC:

AN:

246218

AF XY:

0.0000747

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000109

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000343

AC:

500

AN:

1456794

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

236

AN XY:

725004

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000619

AC:

AN:

48470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000442

AC:

492

AN:

1111930

Other (OTH)

AF:

0.0000663

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000151

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.000168

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 8 (3)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.13

MutationAssessor

Pathogenic

3.8

PhyloP100

8.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0030

Polyphen

0.98

Vest4

0.88

MVP

0.80

MPC

2.0

ClinPred

0.96

GERP RS

3.7

PromoterAI

0.0098

Neutral

(source)

Varity_R

0.97

gMVP

0.94

Mutation Taster

=41/59

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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