rs200810691

chr3-42685815-C-Gchr3-42685815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_152393.4(KLHL40):c.197C>G(p.Pro66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,612,560 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P66L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.81

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 0 ACMG points.

• PM1: In a domain BTB (size 65) in uniprot entity KLH40_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_152393.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01685232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.197C>G	p.Pro66Arg	missense_variant	1/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.197C>G	p.Pro66Arg	missense_variant	1/6	1	NM_152393.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000268 AC: 66 AN: 246042 Hom.: 0 AF XY: 0.000396 AC XY: 53 AN XY: 133964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0000941

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1460418 Hom.: 1 Cov.: 30 AF XY: 0.000224 AC XY: 163 AN XY: 726532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.0000571

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2022

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 66 of the KLHL40 protein (p.Pro66Arg). This variant is present in population databases (rs200810691, gnomAD 0.1%). 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: 541332). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.070
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.58	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.080
Sift	Benign	0.38	T
Sift4G	Benign	0.43	T
Polyphen		0.45	B
Vest4		0.27
MVP		0.54
MPC		1.1
ClinPred		0.060	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.36

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: rs200810691; hg19: chr3-42727307;