rs145851613

Variant names:

• chr11-72093668-C-T
• rs145851613
• NM_145309.6:c.255C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_145309.6(LRRC51):​c.255C>T​(p.Asp85Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,200 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (12 hom.)
• Consequence: LRRC51 NM_145309.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.956
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-72093668-C-T is Benign according to our data. Variant chr11-72093668-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305986.
• BP7: Synonymous conserved (PhyloP=0.956 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

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.255C>T	p.Asp85Asp	synonymous	Exon 4 of 6	NP_660352.1	Q96E66-1
	LRRC51	NM_001318803.2		c.255C>T	p.Asp85Asp	synonymous	Exon 4 of 6	NP_001305732.1	Q96E66-1
	LRRC51	NM_001205138.4		c.201C>T	p.Asp67Asp	synonymous	Exon 3 of 5	NP_001192067.1	Q96E66-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	ENST00000289488.8	TSL:1 MANE Select	c.255C>T	p.Asp85Asp	synonymous	Exon 4 of 6	ENSP00000289488.2	Q96E66-1
	LRRC51	ENST00000541614.5	TSL:1	c.255C>T	p.Asp85Asp	synonymous	Exon 3 of 5	ENSP00000438522.1	Q96E66-2
	LRRC51	ENST00000324866.11	TSL:1	c.255C>T	p.Asp85Asp	synonymous	Exon 4 of 5	ENSP00000440693.1	Q96E66-3

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00311 AC: 783 AN: 251482 AF XY: 0.00326

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00275 AC: 4018 AN: 1461892 Hom.: 12 Cov.: 32 AF XY: 0.00278 AC XY: 2023 AN XY: 727248

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00402 AC: 347 AN: 86258

European-Finnish (FIN) AF: 0.00870 AC: 465 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00260 AC: 2896 AN: 1112010

Other (OTH) AF: 0.00250 AC: 151 AN: 60396

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74464

African (AFR) AF: 0.000481 AC: 20 AN: 41574

American (AMR) AF: 0.00196 AC: 30 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00830 AC: 88 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00275 AC: 187 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00241 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00397

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autosomal recessive nonsyndromic hearing loss 63 (2)
-	-	2	not provided (2)
-	-	1	LRTOMT-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.57
PhyloP100		0.96
Mutation Taster		=297/3	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: rs145851613; hg19: chr11-71804714;