ENST00000307198.11:c.69G>C

Variant names:

• chr11-72104998-G-C
• rs12272086
• ENST00000307198.11:c.69G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000307198.11(LRTOMT):​c.69G>C​(p.Leu23Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,550,840 control chromosomes in the GnomAD database, including 2,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (652 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1938 hom.)
• Consequence: LRTOMT ENST00000307198.11 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.295
• Publications: 10 publications found

Genes affected

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]

TOMT (HGNC:55527): (transmembrane O-methyltransferase) This gene encodes a catechol-O-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a hydroxyl group of catechols and is essential for auditory and vestibular function. Mutations in this gene have been associated with nonsyndromic deafness. Readthrough transcription is observed across this gene and the adjacent leucine-rich repeat containing 51 gene. A third locus (GeneID:220074) is defined to represent the readthrough transcripts. [provided by RefSeq, Feb 2021]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-72104998-G-C is Benign according to our data. Variant chr11-72104998-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307198.11. 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
	LRTOMT	NM_001145308.5		c.69G>C	p.Leu23Leu	synonymous	Exon 4 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.69G>C	p.Leu23Leu	synonymous	Exon 6 of 9	NP_001138781.1
	LRTOMT	NM_001145310.4		c.69G>C	p.Leu23Leu	synonymous	Exon 6 of 9	NP_001138782.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRTOMT	ENST00000307198.11	TSL:2	c.69G>C	p.Leu23Leu	synonymous	Exon 4 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.472G>C		non_coding_transcript_exon	Exon 6 of 9	ENSP00000409403.2
	LRTOMT	ENST00000544409.5	TSL:1	n.472G>C		non_coding_transcript_exon	Exon 6 of 9	ENSP00000440969.1

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11125 AN: 152068 Hom.: 651 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.0426

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0525

GnomAD2 exomes AF: 0.0681 AC: 10519 AN: 154352 AF XY: 0.0674

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0426

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0490

GnomAD4 exome AF: 0.0357 AC: 49959 AN: 1398654 Hom.: 1938 Cov.: 31 AF XY: 0.0374 AC XY: 25770 AN XY: 689802

African (AFR) AF: 0.135 AC: 4249 AN: 31576

American (AMR) AF: 0.121 AC: 4319 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 1042 AN: 25158

East Asian (EAS) AF: 0.160 AC: 5695 AN: 35698

South Asian (SAS) AF: 0.105 AC: 8303 AN: 79100

European-Finnish (FIN) AF: 0.0322 AC: 1588 AN: 49264

Middle Eastern (MID) AF: 0.0304 AC: 173 AN: 5696

European-Non Finnish (NFE) AF: 0.0203 AC: 21945 AN: 1078548

Other (OTH) AF: 0.0456 AC: 2645 AN: 57970

GnomAD4 genome AF: 0.0733 AC: 11149 AN: 152186 Hom.: 652 Cov.: 32 AF XY: 0.0774 AC XY: 5755 AN XY: 74398

African (AFR) AF: 0.133 AC: 5510 AN: 41484

American (AMR) AF: 0.142 AC: 2176 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 148 AN: 3472

East Asian (EAS) AF: 0.156 AC: 807 AN: 5180

South Asian (SAS) AF: 0.114 AC: 550 AN: 4822

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10602

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0216 AC: 1467 AN: 68018

Other (OTH) AF: 0.0515 AC: 109 AN: 2116

Alfa AF: 0.0332 Hom.: 44

Bravo AF: 0.0800

Asia WGS AF: 0.120 AC: 420 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Uncertain	0.98
PhyloP100		0.29
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: rs12272086; hg19: chr11-71816044; COSMIC: COSV53825503; COSMIC: COSV53825503;