chr3-42686652-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152393.4(KLHL40):c.1034A>G(p.Asn345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,613,712 control chromosomes in the GnomAD database, including 335,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27131 hom., cov: 32)

Exomes 𝑓: 0.65 ( 308161 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.53

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.3676526E-7).

BP6

Variant 3-42686652-A-G is Benign according to our data. Variant chr3-42686652-A-G is described in ClinVar as [Benign]. Clinvar id is 226688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-42686652-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL40	NM_152393.4 link	c.1034A>G	p.Asn345Ser	missense_variant	Exon 1 of 6	ENST00000287777.5	NP_689606.2	Q2TBA0-1A8K5H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5 link	c.1034A>G	p.Asn345Ser	missense_variant	Exon 1 of 6	1	NM_152393.4	ENSP00000287777.4		Q2TBA0-1

Frequencies

GnomAD3 genomes

AF:

0.584

AC:

88824

AN:

152006

Hom.:

27120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.516

Gnomad AMR

AF:

0.592

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.815

Gnomad SAS

AF:

0.706

Gnomad FIN

AF:

0.714

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.603

GnomAD3 exomes

AF:

0.651

AC:

163595

AN:

251298

Hom.:

54161

AF XY:

0.659

AC XY:

89484

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.397

Gnomad AMR exome

AF:

0.605

Gnomad ASJ exome

AF:

0.621

Gnomad EAS exome

AF:

0.826

Gnomad SAS exome

AF:

0.698

Gnomad FIN exome

AF:

0.718

Gnomad NFE exome

AF:

0.650

Gnomad OTH exome

AF:

0.647

GnomAD4 exome

AF:

0.647

AC:

945928

AN:

1461588

Hom.:

308161

Cov.:

AF XY:

0.650

AC XY:

472557

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.394

Gnomad4 AMR exome

AF:

0.602

Gnomad4 ASJ exome

AF:

0.627

Gnomad4 EAS exome

AF:

0.793

Gnomad4 SAS exome

AF:

0.696

Gnomad4 FIN exome

AF:

0.721

Gnomad4 NFE exome

AF:

0.645

Gnomad4 OTH exome

AF:

0.640

GnomAD4 genome

AF:

0.584

AC:

88878

AN:

152124

Hom.:

27131

Cov.:

AF XY:

0.591

AC XY:

43988

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.592

Gnomad4 ASJ

AF:

0.614

Gnomad4 EAS

AF:

0.814

Gnomad4 SAS

AF:

0.705

Gnomad4 FIN

AF:

0.714

Gnomad4 NFE

AF:

0.647

Gnomad4 OTH

AF:

0.600

Alfa

AF:

0.628

Hom.:

39338

Bravo

AF:

0.566

TwinsUK

AF:

0.648

AC:

2403

ALSPAC

AF:

0.652

AC:

2513

ESP6500AA

AF:

0.415

AC:

1828

ESP6500EA

AF:

0.634

AC:

5454

ExAC

AF:

0.648

AC:

78736

Asia WGS

AF:

0.725

AC:

2524

AN:

3478

EpiCase

AF:

0.645

EpiControl

AF:

0.648

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asn345Ser in exon 1 of KLHL40: This variant is not expected to have clinical sig nificance because it has been identified in 41.5% (1828/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs6805421). -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 8

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.013

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.68

MetaRNN

Benign

6.4e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

PrimateAI

Benign

0.35

PROVEAN

Benign

0.42

REVEL

Benign

0.12

Sift

Benign

0.54

Sift4G

Benign

0.46

Polyphen

0.0020

Vest4

0.025

MPC

0.055

ClinPred

0.0023

GERP RS

3.2

Varity_R

0.045

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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