3-42686266-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_152393.4(KLHL40):c.648G>T(p.Ala216Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,557,172 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 6 hom. )

Consequence

KLHL40
NM_152393.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.861

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 3-42686266-G-T is Benign according to our data. Variant chr3-42686266-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.861 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0007 (983/1404824) while in subpopulation MID AF = 0.00259 (13/5026). AF 95% confidence interval is 0.00153. There are 6 homozygotes in GnomAdExome4. There are 486 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL40	NM_152393.4 link	c.648G>T	p.Ala216Ala	synonymous_variant	Exon 1 of 6	ENST00000287777.5	NP_689606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5 link	c.648G>T	p.Ala216Ala	synonymous_variant	Exon 1 of 6	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00103

AC:

175

AN:

169330

AF XY:

0.000981

show subpopulations

Gnomad AFR exome

AF:

0.000289

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000700

AC:

983

AN:

1404824

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

486

AN XY:

693542

show subpopulations

African (AFR)

AF:

0.000188

AC:

AN:

31992

American (AMR)

AF:

0.000379

AC:

AN:

36940

Ashkenazi Jewish (ASJ)

AF:

0.0000406

AC:

AN:

24612

East Asian (EAS)

AF:

0.00

AC:

AN:

36784

South Asian (SAS)

AF:

0.000965

AC:

AN:

80808

European-Finnish (FIN)

AF:

0.00217

AC:

102

AN:

46952

Middle Eastern (MID)

AF:

0.00259

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

0.000670

AC:

726

AN:

1083744

Other (OTH)

AF:

0.000742

AC:

AN:

57966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000729

AC:

111

AN:

152348

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41588

American (AMR)

AF:

0.000849

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00102

Hom.:

Bravo

AF:

0.000552

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 02, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KLHL40: BP4, BP7

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 31, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline myopathy 8

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.2

(source)

DANN

Benign

0.91

PhyloP100

-0.86

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over