rs139268932

Variant names:

• chr3-42690960-C-T
• rs139268932
• NM_152393.4:c.1709C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152393.4(KLHL40):​c.1709C>T​(p.Thr570Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T570T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.39
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11816746).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	NM_152393.4	MANE Select	c.1709C>T	p.Thr570Met	missense	Exon 5 of 6	NP_689606.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL40	ENST00000287777.5	TSL:1 MANE Select	c.1709C>T	p.Thr570Met	missense	Exon 5 of 6	ENSP00000287777.4	Q2TBA0-1
	KLHL40	ENST00000942348.1		c.1694C>T	p.Thr565Met	missense	Exon 5 of 6	ENSP00000612407.1
	KLHL40	ENST00000942349.1		c.1688C>T	p.Thr563Met	missense	Exon 5 of 6	ENSP00000612408.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000152 AC: 38 AN: 250786 AF XY: 0.000155

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461300 Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 726980

African (AFR) AF: 0.000329 AC: 11 AN: 33470

American (AMR) AF: 0.000470 AC: 21 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1111650

Other (OTH) AF: 0.000182 AC: 11 AN: 60362

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74438

African (AFR) AF: 0.000241 AC: 10 AN: 41554

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Nemaline myopathy 8 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.11	T
Polyphen		0.71	P
Vest4		0.53
MVP		0.72
MPC		0.12
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.053
gMVP		0.38
Mutation Taster		=97/3	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: rs139268932; hg19: chr3-42732452; COSMIC: COSV55132895; COSMIC: COSV55132895;