rs201856772

Positions:

• chr3-42691889-G-A
• chr3-42691889-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_152393.4(KLHL40):​c.1762G>A​(p.Glu588Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00047 in 1,598,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.41

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035648078).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00165 (244/147654) while in subpopulation AFR AF= 0.00531 (198/37258). AF 95% confidence interval is 0.00471. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.1762G>A	p.Glu588Lys	missense_variant	6/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.1762G>A	p.Glu588Lys	missense_variant	6/6	1	NM_152393.4	P1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 245 AN: 147540 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000990

GnomAD3 exomes AF: 0.000663 AC: 166 AN: 250232 Hom.: 0 AF XY: 0.000576 AC XY: 78 AN XY: 135320

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00158

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000349 AC: 507 AN: 1450760 Hom.: 2 Cov.: 29 AF XY: 0.000332 AC XY: 240 AN XY: 722738

Gnomad4 AFR exome AF: 0.00453

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.00165 AC: 244 AN: 147654 Hom.: 0 Cov.: 31 AF XY: 0.00172 AC XY: 124 AN XY: 72266

Gnomad4 AFR AF: 0.00531

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.000979

Alfa AF: 0.000456 Hom.: 0

Bravo AF: 0.00194

ExAC AF: 0.000816 AC: 98

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2021

- -

Nemaline myopathy 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.82
MVP		0.86
MPC		0.30
ClinPred		0.023	T
GERP RS		3.3
Varity_R		0.40
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201856772; hg19: chr3-42733381; COSMIC: COSV99040153; COSMIC: COSV99040153;