11-72106006-C-A

Variant names:

• chr11-72106006-C-A
• rs1372399805
• NM_001393500.2:c.55C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001393500.2(TOMT):​c.55C>A​(p.Arg19Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,580 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TOMT NM_001393500.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

Genes affected

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]

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP7: Synonymous conserved (PhyloP=2.01 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393500.2. 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
	TOMT	NM_001393500.2	MANE Select	c.55C>A	p.Arg19Arg	synonymous	Exon 1 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.154C>A	p.Arg52Arg	synonymous	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.154C>A	p.Arg52Arg	synonymous	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.55C>A	p.Arg19Arg	synonymous	Exon 1 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000307198.11	TSL:2	c.154C>A	p.Arg52Arg	synonymous	Exon 5 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.557C>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398580 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689848

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.0000280 AC: 1 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078942

Other (OTH) AF: 0.00 AC: 0 AN: 57956

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.7
DANN	Benign	0.92
PhyloP100		2.0
PromoterAI		0.024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1372399805; hg19: chr11-71817052;