rs140389534

Variant names:

• chr3-42688651-T-C
• rs140389534
• NM_152393.4:c.1355T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_152393.4(KLHL40):​c.1355T>C​(p.Val452Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V452V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.89
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000588 (86/1461748) while in subpopulation MID AF = 0.00295 (17/5768). AF 95% confidence interval is 0.00188. There are 0 homozygotes in GnomAdExome4. There are 38 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1355T>C	p.Val452Ala	missense	Exon 3 of 6	NP_689606.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1355T>C	p.Val452Ala	missense	Exon 3 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1340T>C	p.Val447Ala	missense	Exon 3 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1355T>C	p.Val452Ala	missense	Exon 3 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251266 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727168

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111982

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74188

African (AFR) AF: 0.000194 AC: 8 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67988

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Nemaline myopathy 8 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.033
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.027	D
Polyphen		0.15	B
Vest4		0.88
MVP		0.81
MPC		0.17
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.66
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs140389534; hg19: chr3-42730143;