rs760524187

Positions:

• chr2-169510204-ACTT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PM4_Supporting BS1_Supporting

The NM_006063.3(KLHL41):​c.433_435del​(p.Leu145del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KLHL41 NM_006063.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.67

Genes affected

KLHL41 (HGNC:16905): (kelch like family member 41) This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain BACK (size 102) in uniprot entity KLH41_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_006063.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006063.3. Strenght limited to Supporting due to length of the change: 1aa.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000472 (69/1461800) while in subpopulation AMR AF= 0.000335 (15/44724). AF 95% confidence interval is 0.000206. There are 0 homozygotes in gnomad4_exome. There are 32 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL41	NM_006063.3	c.433_435del	p.Leu145del	inframe_deletion	1/6	ENST00000284669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL41	ENST00000284669.2	c.433_435del	p.Leu145del	inframe_deletion	1/6	1	NM_006063.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000638 AC: 16 AN: 250720 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135780

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461800 Hom.: 0 AF XY: 0.0000440 AC XY: 32 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	This variant, c.433_435del, results in the deletion of 1 amino acid(s) of the KLHL41 protein (p.Leu145del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760524187, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KLHL41-related conditions. ClinVar contains an entry for this variant (Variation ID: 474872). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2022

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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: rs760524187; hg19: chr2-170366714;