rs397509419

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_152393.4(KLHL40):c.1582G>A(p.Glu528Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,776 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.84

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a repeat Kelch 4 (size 45) in uniprot entity KLH40_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_152393.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 3-42689029-G-A is Pathogenic according to our data. Variant chr3-42689029-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-42689029-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4 linkuse as main transcript	c.1582G>A	p.Glu528Lys	missense_variant	4/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5 linkuse as main transcript	c.1582G>A	p.Glu528Lys	missense_variant	4/6	1	NM_152393.4	P1	Q2TBA0-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250842

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 8

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic supporitng evidence (ClinVar ID: VCV000060512.2, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000637, PM2). The variant was observed in trans with a pathogenic variant (NM_152393.3:c.1281_1294del) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.875, PP3). Patient's phenotype is considered compatible with Nemaline myopathy 8, autosomal recessive (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 20, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 528 of the KLHL40 protein (p.Glu528Lys). This variant is present in population databases (rs397509419, gnomAD 0.09%). This missense change has been observed in individuals with nemaline myopathy (PMID: 23746549). ClinVar contains an entry for this variant (Variation ID: 60512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change alters KLHL40 gene expression (PMID: 24960163). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.31

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.95

MutPred

0.73

Gain of ubiquitination at E528 (P = 0.0203);

MVP

0.92

MPC

0.42

ClinPred

0.94

GERP RS

4.4

Varity_R

0.84

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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