chr11-72106051-C-T

Variant names:

• chr11-72106051-C-T
• rs780468292
• NM_001393500.2:c.100C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001393500.2(TOMT):​c.100C>T​(p.Arg34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,398,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: TOMT NM_001393500.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.60
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72106051-C-T is Pathogenic according to our data. Variant chr11-72106051-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1804950.Status of the report is criteria_provided_single_submitter, 1 stars.

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.100C>T	p.Arg34*	stop_gained	Exon 1 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.199C>T	p.Arg67*	stop_gained	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.199C>T	p.Arg67*	stop_gained	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.100C>T	p.Arg34*	stop_gained	Exon 1 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000307198.11	TSL:2	c.199C>T	p.Arg67*	stop_gained	Exon 5 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.602C>T		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000647 AC: 1 AN: 154444 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398510 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 689828

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.0000560 AC: 2 AN: 35700

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

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078966

Other (OTH) AF: 0.00 AC: 0 AN: 57996

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000388 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 63 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.76	D
PhyloP100		1.6
Vest4		0.31
GERP RS		1.0
PromoterAI		-0.0072	Neutral
Mutation Taster		=26/174	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780468292; hg19: chr11-71817097; COSMIC: COSV107188287; COSMIC: COSV107188287;