11-72106006-C-T

Variant names:

• chr11-72106006-C-T
• rs1372399805
• NM_001393500.2:c.55C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001393500.2(TOMT):​c.55C>T​(p.Arg19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,398,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.01

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
• PP5: Variant 11-72106006-C-T is Pathogenic according to our data. Variant chr11-72106006-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1333659.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.55C>T	p.Arg19Trp	missense_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.154C>T	p.Arg52Trp	missense_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.154C>T	p.Arg52Trp	missense_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.84-50C>T		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.55C>T	p.Arg19Trp	missense_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.154C>T	p.Arg52Trp	missense_variant	Exon 5 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000130 AC: 2 AN: 153986 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 81756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000183

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: 0.00000429 AC: 6 AN: 1398580 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63 Pathogenic:1 Uncertain:1

Jan 03, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000013, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.635, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.0067
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.89
MutPred		0.52		Gain of catalytic residue at L50 (P = 0.0032);Gain of catalytic residue at L50 (P = 0.0032);.;
MVP		0.92
MPC		0.39
ClinPred		0.84	D
GERP RS		0.99
Varity_R		0.19
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1372399805; hg19: chr11-71817052; COSMIC: COSV99597694; COSMIC: COSV99597694;