3-42691928-G-T

Variant names:

• chr3-42691928-G-T
• rs144659891
• NM_152393.4:c.1801G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152393.4(KLHL40):​c.1801G>T​(p.Ala601Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A601T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.536
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nemaline myopathy 8

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07390347).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152393.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1801G>T	p.Ala601Ser	missense	Exon 6 of 6	NP_689606.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1801G>T	p.Ala601Ser	missense	Exon 6 of 6	ENSP00000287777.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 8 Uncertain:1

Mar 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 601 of the KLHL40 protein (p.Ala601Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant has not been reported in the literature in individuals with KLHL40-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.54
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.042
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.42		Gain of sheet (P = 0.1208)
MVP		0.33
MPC		0.061
ClinPred		0.081	T
GERP RS		-1.8
Varity_R		0.11
gMVP		0.29
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs144659891; hg19: chr3-42733420;