11-72106007-G-A

Variant names:

• chr11-72106007-G-A
• rs950057959
• NM_001393500.2:c.56G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001393500.2(TOMT):​c.56G>A​(p.Arg19Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000368 in 1,550,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.56G>A	p.Arg19Gln	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.155G>A	p.Arg52Gln	missense_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.155G>A	p.Arg52Gln	missense_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.84-49G>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.56G>A	p.Arg19Gln	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.155G>A	p.Arg52Gln	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 17 AN: 154052 Hom.: 0 AF XY: 0.0000734 AC XY: 6 AN XY: 81784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000689

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: 0.0000393 AC: 55 AN: 1398658 Hom.: 0 Cov.: 31 AF XY: 0.0000377 AC XY: 26 AN XY: 689894

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000616

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: 0.0000278

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.099	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.72	N;N;.
REVEL	Benign	0.22
Sift	Benign	0.16	T;T;.
Sift4G	Benign	0.22	T;T;.
Polyphen		0.0070	B;B;.
Vest4		0.66
MutPred		0.56		Loss of methylation at R52 (P = 0.0067);Loss of methylation at R52 (P = 0.0067);.;
MVP		0.84
MPC		0.41
ClinPred		0.23	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs950057959; hg19: chr11-71817053;