rs138791086

Positions:

• chr3-42688262-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 2.88

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 -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: {Likely_benign=4, Uncertain_significance=2}.
• 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	Protein	UniProt
KLHL40	NM_152393.4	c.1273G>A	p.Gly425Ser	missense_variant	2/6	ENST00000287777.5	NP_689606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5	c.1273G>A	p.Gly425Ser	missense_variant	2/6	1	NM_152393.4	ENSP00000287777.4

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152070 Hom.: 0 Cov.: 31

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.: 1 AF XY: 0.000957 AC XY: 130 AN XY: 135860

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.: 4 Cov.: 32 AF XY: 0.00115 AC XY: 835 AN XY: 727214

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.: 0 Cov.: 31 AF XY: 0.000780 AC XY: 58 AN XY: 74382

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.: 1

Bravo AF: 0.000767

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 8 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -
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]. -

not provided Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 21, 2019	- -

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	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.093
Sift	Benign	0.37	T
Sift4G	Benign	0.64	T
Polyphen		0.11	B
Vest4		0.27
MVP		0.78
MPC		0.068
ClinPred		0.021	T
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

Other links and lift over

dbSNP: rs138791086; hg19: chr3-42729754;