11-72106043-T-C

Variant names:

• chr11-72106043-T-C
• rs574631765
• NM_001393500.2:c.92T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393500.2(TOMT):​c.92T>C​(p.Val31Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V31G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.92T>C	p.Val31Ala	missense	Exon 1 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.191T>C	p.Val64Ala	missense	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.191T>C	p.Val64Ala	missense	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.92T>C	p.Val31Ala	missense	Exon 1 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000307198.11	TSL:2	c.191T>C	p.Val64Ala	missense	Exon 5 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.594T>C		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.60
Sift	Benign	0.17	T
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.43		Gain of helix (P = 0.0117)
MVP		0.91
MPC		0.41
ClinPred		0.96	D
GERP RS		4.4
PromoterAI		0.030	Neutral
Varity_R		0.12
gMVP		0.76
Mutation Taster		=24/76	disease causing

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: rs574631765; hg19: chr11-71817089;