rs140389534

chr3-42688651-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

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:2
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.1355T>C	p.Val452Ala	missense_variant	3/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.1355T>C	p.Val452Ala	missense_variant	3/6	1	NM_152393.4	P1

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

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251266 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135790

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 SAS 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

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000199

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

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 2016

- -

Nemaline myopathy 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 452 of the KLHL40 protein (p.Val452Ala). This variant is present in population databases (rs140389534, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KLHL40-related conditions. ClinVar contains an entry for this variant (Variation ID: 447661). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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

LitVar

Other links and lift over

dbSNP: rs140389534; hg19: chr3-42730143;