3-42686652-A-G

Variant names:

• chr3-42686652-A-G
• rs6805421
• NM_152393.4:c.1034A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.53
• Publications: 33 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.1034A>G	p.Asn345Ser	missense_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	c.1034A>G	p.Asn345Ser	missense_variant	Exon 1 of 6	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88824 AN: 152006 Hom.: 27120 Cov.: 32

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

GnomAD2 exomes AF: 0.651 AC: 163595 AN: 251298 AF XY: 0.659

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 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.: 59 AF XY: 0.650 AC XY: 472557 AN XY: 727082

African (AFR) AF: 0.394 AC: 13190 AN: 33480

American (AMR) AF: 0.602 AC: 26914 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 16385 AN: 26132

East Asian (EAS) AF: 0.793 AC: 31493 AN: 39700

South Asian (SAS) AF: 0.696 AC: 60048 AN: 86256

European-Finnish (FIN) AF: 0.721 AC: 38358 AN: 53206

Middle Eastern (MID) AF: 0.638 AC: 3679 AN: 5766

European-Non Finnish (NFE) AF: 0.645 AC: 717239 AN: 1111936

Other (OTH) AF: 0.640 AC: 38622 AN: 60392

GnomAD4 genome AF: 0.584 AC: 88878 AN: 152124 Hom.: 27131 Cov.: 32 AF XY: 0.591 AC XY: 43988 AN XY: 74392

African (AFR) AF: 0.400 AC: 16617 AN: 41516

American (AMR) AF: 0.592 AC: 9057 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2131 AN: 3468

East Asian (EAS) AF: 0.814 AC: 4207 AN: 5166

South Asian (SAS) AF: 0.705 AC: 3402 AN: 4824

European-Finnish (FIN) AF: 0.714 AC: 7552 AN: 10578

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43987 AN: 67964

Other (OTH) AF: 0.600 AC: 1267 AN: 2112

Alfa AF: 0.626 Hom.: 97527

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

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	6.4e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.12
Sift	Benign	0.54	T
Sift4G	Benign	0.46	T
Vest4		0.025
ClinPred		0.0023	T
GERP RS		3.2
Varity_R		0.045
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6805421; hg19: chr3-42728144; COSMIC: COSV55133361;