rs138791086

Positions:

chr3-42688262-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152393.4(KLHL40):c.1273G>A(p.Gly425Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,998 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G425G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 2.88

Variant links:

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]

KLHL40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01951465).

BP6

Variant 3-42688262-G-A is Benign according to our data. Variant chr3-42688262-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474324.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00116 (1693/1461810) while in subpopulation EAS AF= 0.00456 (181/39700). AF 95% confidence interval is 0.00402. There are 4 homozygotes in gnomad4_exome. There are 835 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4 linkuse as main transcript	c.1273G>A	p.Gly425Ser	missense_variant	2/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5 linkuse as main transcript	c.1273G>A	p.Gly425Ser	missense_variant	2/6	1	NM_152393.4	P1	Q2TBA0-1

Frequencies

GnomAD3 genomes

AF:

0.000809

AC:

123

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.000963

AC:

242

AN:

251234

Hom.:

AF XY:

0.000957

AC XY:

130

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00116

AC:

1693

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

835

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00456

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152188

Hom.:

Cov.:

AF XY:

0.000780

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000775

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 8

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 03, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KLHL40 p.Gly425Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs138791086) and ClinVar (classified as uncertian significance by Invitae). The variant was identified in control databases in 271 of 282578 chromosomes (1 homozygous) at a frequency of 0.000959 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 14 of 7224 chromosomes (freq: 0.001938), Latino in 52 of 35432 chromosomes (freq: 0.001468), European (non-Finnish) in 182 of 128968 chromosomes (freq: 0.001411), East Asian in 8 of 19944 chromosomes (freq: 0.000401), African in 8 of 24916 chromosomes (freq: 0.000321), European (Finnish) in 4 of 25116 chromosomes (freq: 0.000159) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the Ashkenazi Jewish population. The p.Gly425 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.1273G>A (p.G425S) alteration is located in exon 2 (coding exon 2) of the KLHL40 gene. This alteration results from a G to A substitution at nucleotide position 1273, causing the glycine (G) at amino acid position 425 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.2

REVEL

Benign

0.093

Sift

Benign

0.37

Sift4G

Benign

0.64

Polyphen

0.11

Vest4

0.27

MVP

0.78

MPC

0.068

ClinPred

0.021

GERP RS

3.1

Varity_R

0.13

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over