NM_145309.6:c.83-1_83delGA

Variant names:

• chr11-72093493-CAG-C
• NM_145309.6:c.83-1_83delGA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_145309.6(LRRC51):​c.83-1_83delGA​(p.Asp28fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC51 NM_145309.6 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.11
• Publications: 0 publications found

Genes affected

LRRC51 (HGNC:55526): (leucine rich repeat containing 51) This gene belongs to the leucine-rich repeat containing family. The encoded protein contains a transmembrane domain and two leucine-rich repeat domains. Unlike in mouse and other mammals, readthrough transcription is observed in primates between this gene and the adjacent transmembrane O-methyltransferase (Tomt) gene. Previously, this locus was annotated as a single gene representing the readthrough transcripts as well as the two different transcript species that encoded different proteins. It has since been split into three genes, including the two stand-alone genes and a third gene representing the readthrough transcription. [provided by RefSeq, Feb 2022]

LRTOMT (HGNC:25033): (leucine rich transmembrane and O-methyltransferase domain containing) This locus represents naturally occurring readthrough transcription between the neighboring LRRC51 (leucine-rich repeat containing 51) and TOMT (transmembrane O-methyltransferase) genes on chromosome 11. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. Multiple reports implicate mutations in this gene in nonsyndromic deafness.[provided by RefSeq, Feb 2021]

LAMTOR1 (HGNC:26068): (late endosomal/lysosomal adaptor, MAPK and MTOR activator 1) Enables GTPase binding activity. Contributes to guanyl-nucleotide exchange factor activity and molecular adaptor activity. Involved in several processes, including cholesterol homeostasis; positive regulation of TOR signaling; and regulation of cholesterol transport. Located in lysosome. Part of Ragulator complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.857 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72093493-CAG-C is Pathogenic according to our data. Variant chr11-72093493-CAG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3075852.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145309.6. 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
	LRRC51	NM_145309.6	MANE Select	c.83-1_83delGA	p.Asp28fs	frameshift splice_acceptor splice_region intron	Exon 4 of 6	NP_660352.1	Q96E66-1
	LRTOMT	NM_001145308.5		c.-321-1_-321delGA		splice_region	Exon 2 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.-321-1_-321delGA		splice_region	Exon 4 of 9	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	ENST00000289488.8	TSL:1 MANE Select	c.83-2_83-1delAG		splice_acceptor intron	N/A	ENSP00000289488.2	Q96E66-1
	LRTOMT	ENST00000307198.11	TSL:2	c.-321-2_-321-1delAG		splice_acceptor intron	N/A	ENSP00000305742.7
	LRRC51	ENST00000541614.5	TSL:1	c.83-2_83-1delAG		splice_acceptor intron	N/A	ENSP00000438522.1	Q96E66-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-71804539;