rs185171192

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_152393.4(KLHL40):c.1313+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,610,830 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

KLHL40
NM_152393.4 splice_region, intron

Scores

Splicing: ADA: 0.0004344

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0540

Publications

0 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 3-42688309-A-G is Benign according to our data. Variant chr3-42688309-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 387671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00242 (367/151398) while in subpopulation AFR AF = 0.00849 (350/41208). AF 95% confidence interval is 0.00776. There are 1 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL40	NM_152393.4 link	c.1313+7A>G		splice_region_variant, intron_variant	Intron 2 of 5	ENST00000287777.5	NP_689606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5 link	c.1313+7A>G		splice_region_variant, intron_variant	Intron 2 of 5	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

366

AN:

151280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00849

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000855

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000607

AC:

152

AN:

250234

AF XY:

0.000457

show subpopulations

Gnomad AFR exome

AF:

0.00870

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000247

AC:

360

AN:

1459432

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

725988

show subpopulations

African (AFR)

AF:

0.00901

AC:

301

AN:

33404

American (AMR)

AF:

0.000336

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110498

Other (OTH)

AF:

0.000581

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00242

AC:

367

AN:

151398

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

170

AN XY:

73984

show subpopulations

African (AFR)

AF:

0.00849

AC:

350

AN:

41208

American (AMR)

AF:

0.000854

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67884

Other (OTH)

AF:

0.00143

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00144

Hom.:

Bravo

AF:

0.00281

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 01, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nemaline myopathy 8

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KLHL40-related disorder

Benign:1

May 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.3

(source)

DANN

Benign

0.49

PhyloP100

-0.054

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.062

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: 29

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over