rs123509

Positions:

• chr3-42691976-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152393.4(KLHL40):​c.1849T>C​(p.Cys617Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,604,172 control chromosomes in the GnomAD database, including 488,773 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C617H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (50950 hom., cov: 32)
  • Exomes 𝑓: 0.77 (437823 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.26

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=5.5673183E-7).
• BP6: Variant 3-42691976-T-C is Benign according to our data. Variant chr3-42691976-T-C is described in ClinVar as [Benign]. Clinvar id is 226689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-42691976-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.1849T>C	p.Cys617Arg	missense_variant	6/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.1849T>C	p.Cys617Arg	missense_variant	6/6	1	NM_152393.4	P1

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123746 AN: 152008 Hom.: 50889 Cov.: 32

Gnomad AFR AF: 0.915

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.807

GnomAD3 exomes AF: 0.815 AC: 204835 AN: 251286 Hom.: 84478 AF XY: 0.811 AC XY: 110125 AN XY: 135796

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.859

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.758

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.774 AC: 1123927 AN: 1452044 Hom.: 437823 Cov.: 31 AF XY: 0.775 AC XY: 560375 AN XY: 723048

Gnomad4 AFR exome AF: 0.916

Gnomad4 AMR exome AF: 0.899

Gnomad4 ASJ exome AF: 0.740

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.856

Gnomad4 FIN exome AF: 0.724

Gnomad4 NFE exome AF: 0.752

Gnomad4 OTH exome AF: 0.785

GnomAD4 genome AF: 0.814 AC: 123867 AN: 152128 Hom.: 50950 Cov.: 32 AF XY: 0.815 AC XY: 60629 AN XY: 74368

Gnomad4 AFR AF: 0.915

Gnomad4 AMR AF: 0.847

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.870

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.804

Alfa AF: 0.773 Hom.: 117580

Bravo AF: 0.830

TwinsUK AF: 0.753 AC: 2792

ALSPAC AF: 0.751 AC: 2895

ESP6500AA AF: 0.904 AC: 3985

ESP6500EA AF: 0.754 AC: 6487

ExAC AF: 0.817 AC: 99138

Asia WGS AF: 0.913 AC: 3176 AN: 3478

EpiCase AF: 0.759

EpiControl AF: 0.770

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Cys617Arg in exon 6 of KLHL40: This variant is not expected to have clinical sig nificance because it has been identified in 24.6% (2113/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs123509). -

Nemaline myopathy 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.44
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.092	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	0.0095	P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	3.9	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.12
ClinPred		0.00035	T
GERP RS		3.3
Varity_R		0.25
gMVP		0.73

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: rs123509; hg19: chr3-42733468;