Genetic Variant KLHL40:p.Ala538Thr (chr3-42690863-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PM5BP4_Strong

The NM_152393.4(KLHL40):c.1612G>A(p.Ala538Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,451,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A538P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.456

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-42690863-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 60515.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.06666225).

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.1612G>A	p.Ala538Thr	missense	Exon 5 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.1612G>A	p.Ala538Thr	missense	Exon 5 of 6	ENSP00000287777.4	Q2TBA0-1
KLHL40	ENST00000942348.1		c.1597G>A	p.Ala533Thr	missense	Exon 5 of 6	ENSP00000612407.1
KLHL40	ENST00000942349.1		c.1591G>A	p.Ala531Thr	missense	Exon 5 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000821

AC:

AN:

243664

AF XY:

0.00000760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.000107

Gnomad EAS 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:

0.00000482

AC:

AN:

1451444

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33210

American (AMR)

AF:

0.0000229

AC:

AN:

43574

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25440

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5098

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1106572

Other (OTH)

AF:

0.00

AC:

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000317

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.11

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.47

M_CAP

Benign

0.061

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.46

PrimateAI

Benign

0.30

PROVEAN

Benign

0.43

REVEL

Benign

0.077

Sift

Benign

0.54

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.13

MutPred

0.39

Loss of catalytic residue at A538 (P = 0.0492)

MVP

0.42

MPC

0.065

ClinPred

0.054

GERP RS

1.2

Varity_R

0.056

gMVP

0.35

Mutation Taster

=44/56

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over