rs3018301

Variant names:

• chr11-72081025-A-G
• rs3018301
• NM_145309.6:c.-140+140A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-72081025-A-G
• chr11-72081025-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145308.5(LRTOMT):​c.-322+140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 152,732 control chromosomes in the GnomAD database, including 52,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (51953 hom., cov: 32)
  • Exomes 𝑓: 0.91 (248 hom.)
• Consequence: LRTOMT NM_001145308.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 6 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]

LRTOMT Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 63

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145308.5. 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.-140+140A>G		intron	N/A	NP_660352.1
	LRTOMT	NM_001145308.5		c.-322+140A>G		intron	N/A	NP_001138780.1
	LRTOMT	NM_001145309.4		c.-543+140A>G		intron	N/A	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC51	ENST00000289488.8	TSL:1 MANE Select	c.-140+140A>G		intron	N/A	ENSP00000289488.2
	LRTOMT	ENST00000307198.11	TSL:2	c.-322+140A>G		intron	N/A	ENSP00000305742.7
	LRRC51	ENST00000324866.11	TSL:1	c.-140+140A>G		intron	N/A	ENSP00000440693.1

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123087 AN: 152034 Hom.: 51951 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.943

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.944

Gnomad OTH AF: 0.854

GnomAD4 exome AF: 0.912 AC: 529 AN: 580 Hom.: 248 AF XY: 0.897 AC XY: 357 AN XY: 398

African (AFR) AF: 0.571 AC: 8 AN: 14

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 4 AN: 6

East Asian (EAS) AF: 0.611 AC: 11 AN: 18

South Asian (SAS) AF: 0.875 AC: 14 AN: 16

European-Finnish (FIN) AF: 0.942 AC: 49 AN: 52

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.933 AC: 388 AN: 416

Other (OTH) AF: 0.942 AC: 49 AN: 52

GnomAD4 genome AF: 0.809 AC: 123118 AN: 152152 Hom.: 51953 Cov.: 32 AF XY: 0.808 AC XY: 60110 AN XY: 74378

African (AFR) AF: 0.550 AC: 22789 AN: 41448

American (AMR) AF: 0.796 AC: 12170 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3154 AN: 3472

East Asian (EAS) AF: 0.769 AC: 3980 AN: 5176

South Asian (SAS) AF: 0.838 AC: 4047 AN: 4832

European-Finnish (FIN) AF: 0.932 AC: 9887 AN: 10610

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.943 AC: 64170 AN: 68014

Other (OTH) AF: 0.857 AC: 1806 AN: 2108

Alfa AF: 0.855 Hom.: 10912

Bravo AF: 0.791

Asia WGS AF: 0.799 AC: 2776 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.68
PhyloP100		-1.0
PromoterAI		0.039	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3018301; hg19: chr11-71792071; COSMIC: COSV56193056;