11-72106061-G-C

Variant names:

• chr11-72106061-G-C
• rs188715129
• NM_001393500.2:c.110G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001393500.2(TOMT):​c.110G>C​(p.Arg37Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,444 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.110G>C	p.Arg37Pro	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.209G>C	p.Arg70Pro	missense_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.209G>C	p.Arg70Pro	missense_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.89G>C	p.Arg30Pro	missense_variant	Exon 7 of 9		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.110G>C	p.Arg37Pro	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.209G>C	p.Arg70Pro	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000646 AC: 1 AN: 154834 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82242

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000143 AC: 2 AN: 1398444 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689798

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Pathogenic	0.74
Sift	Benign	0.053	T;T;.
Sift4G	Benign	0.10	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.53
MutPred		0.63		Loss of MoRF binding (P = 0.002);Loss of MoRF binding (P = 0.002);.;
MVP		0.88
MPC		0.28
ClinPred		0.59	D
GERP RS		4.4
Varity_R		0.58
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs188715129; hg19: chr11-71817107;