rs149980411

chr3-42690989-C-Achr3-42690989-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152393.4(KLHL40):c.1738C>A(p.Leu580Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,610,860 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (44 hom.)
• Consequence: KLHL40 NM_152393.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.04

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=0.009362847).
• BP6: Variant 3-42690989-C-A is Benign according to our data. Variant chr3-42690989-C-A is described in ClinVar as [Benign]. Clinvar id is 262642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-42690989-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000985 (150/152244) while in subpopulation SAS AF= 0.0208 (100/4818). AF 95% confidence interval is 0.0175. There are 3 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL40	NM_152393.4	c.1738C>A	p.Leu580Ile	missense_variant	5/6	ENST00000287777.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL40	ENST00000287777.5	c.1738C>A	p.Leu580Ile	missense_variant	5/6	1	NM_152393.4	P1

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00342 AC: 848 AN: 247750 Hom.: 13 AF XY: 0.00464 AC XY: 622 AN XY: 133946

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00257

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000661

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00178 AC: 2593 AN: 1458616 Hom.: 44 Cov.: 31 AF XY: 0.00250 AC XY: 1815 AN XY: 725484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00294

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000259

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74430

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 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. -

Nemaline myopathy 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.27
Sift	Benign	0.26	T
Sift4G	Benign	0.21	T
Polyphen		0.0080	B
Vest4		0.44
MVP		0.74
MPC		0.10
ClinPred		0.019	T
GERP RS		2.9
Varity_R		0.24
gMVP		0.29

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: rs149980411; hg19: chr3-42732481;