rs74843241

Positions:

• chr3-42686490-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152393.4(KLHL40):​c.872A>C​(p.Lys291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,126 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (68 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.643

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030818582).
• BP6: Variant 3-42686490-A-C is Benign according to our data. Variant chr3-42686490-A-C is described in ClinVar as [Benign]. Clinvar id is 262646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00238 (362/152306) while in subpopulation EAS AF= 0.0447 (232/5186). AF 95% confidence interval is 0.04. There are 10 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.872A>C	p.Lys291Thr	missense_variant	1/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.872A>C	p.Lys291Thr	missense_variant	1/6	1	NM_152393.4	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152188 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00546 AC: 1371 AN: 251198 Hom.: 30 AF XY: 0.00494 AC XY: 670 AN XY: 135746

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0424

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00192 AC: 2811 AN: 1461820 Hom.: 68 Cov.: 30 AF XY: 0.00185 AC XY: 1344 AN XY: 727200

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0478

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152306 Hom.: 10 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74482

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0447

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00207 Hom.: 9

Bravo AF: 0.00329

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00544 AC: 661

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nemaline myopathy 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.9
DANN	Benign	0.37
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.057
Sift	Benign	0.56	T
Sift4G	Benign	0.51	T
Polyphen		0.0060	B
Vest4		0.23
MVP		0.53
MPC		0.082
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.038
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74843241; hg19: chr3-42727982;