chr11-72106040-C-A

Variant names:

• chr11-72106040-C-A
• rs876657502
• NM_001393500.2:c.89C>A

Variant summary

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

The NM_001393500.2(TOMT):​c.89C>A​(p.Thr30Lys) 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 1,398,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 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. T30M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.89C>A	p.Thr30Lys	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.188C>A	p.Thr63Lys	missense_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.188C>A	p.Thr63Lys	missense_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.84-16C>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.89C>A	p.Thr30Lys	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.188C>A	p.Thr63Lys	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689938

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35702

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078968

Other (OTH) AF: 0.00 AC: 0 AN: 57998

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.056	T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L;L;.
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.21	N;N;.
REVEL	Benign	0.24
Sift	Benign	0.54	T;T;.
Sift4G	Benign	0.83	T;T;.
Polyphen		0.026	B;B;.
Vest4		0.41
MutPred		0.41		Gain of methylation at T63 (P = 0.0499);Gain of methylation at T63 (P = 0.0499);.;
MVP		0.58
MPC		0.086
ClinPred		0.15	T
GERP RS		0.21
PromoterAI		0.022	Neutral
Varity_R		0.057
gMVP		0.67
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876657502; hg19: chr11-71817086;