NM_001393500.2:c.19T>A

Variant names:

• chr11-72105970-T-A
• rs876657501
• NM_001393500.2:c.19T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393500.2(TOMT):​c.19T>A​(p.Leu7Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,642 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. Synonymous variant affecting the same amino acid position (i.e. L7L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.694
• 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 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24738753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.19T>A	p.Leu7Met	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.118T>A	p.Leu40Met	missense_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.118T>A	p.Leu40Met	missense_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.84-86T>A		intron_variant	Intron 6 of 8		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.19T>A	p.Leu7Met	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.118T>A	p.Leu40Met	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397642 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689326

African (AFR) AF: 0.00 AC: 0 AN: 31552

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4558

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078722

Other (OTH) AF: 0.00 AC: 0 AN: 57862

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.80	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		0.69
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.64	N;N;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.038	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.34		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;
MVP		0.58
MPC		0.38
ClinPred		0.71	D
GERP RS		1.3
PromoterAI		0.026	Neutral
Varity_R		0.15
gMVP		0.75
Mutation Taster		=95/5	polymorphism

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: rs876657501; hg19: chr11-71817016;