rs545947177

Positions:

• chr11-72106214-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001393500.2(TOMT):​c.259+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,480,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TOMT NM_001393500.2 splice_region, intron
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.18

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72106214-A-C is Pathogenic according to our data. Variant chr11-72106214-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72106214-A-C is described in Lovd as [Likely_pathogenic]. Variant chr11-72106214-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.259+4A>C		splice_region_variant, intron_variant		ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.358+4A>C		splice_region_variant, intron_variant			NP_001138780.1
LRTOMT	NM_001145309.4	c.358+4A>C		splice_region_variant, intron_variant			NP_001138781.1
LRTOMT	NM_001145310.4	c.238+4A>C		splice_region_variant, intron_variant			NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.259+4A>C		splice_region_variant, intron_variant		5	NM_001393500.2	ENSP00000494667.1
LRTOMT	ENST00000307198.11	c.358+4A>C		splice_region_variant, intron_variant		2		ENSP00000305742.7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000451 AC: 5 AN: 110756 Hom.: 0 AF XY: 0.0000521 AC XY: 3 AN XY: 57530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000983

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: 0.0000682

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 17 AN: 1327804 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 9 AN XY: 646398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000642

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000497 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 63 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2008

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

This sequence change falls in intron 5 of the LRTOMT gene. It does not directly change the encoded amino acid sequence of the LRTOMT protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs545947177, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 17211611, 18953341). ClinVar contains an entry for this variant (Variation ID: 179792). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 (also known as exon 8) and introduces a new termination codon (PMID: 18953341). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the LRTOMT protein in which other variant(s) (p.Arg219*) have been determined to be pathogenic (PMID: 26166082, 26969326, 35939872). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2014

The 358+4A>C variant in LRTOMT has been reported in a Turkish family with hearin g loss (Ahmed 2008, Kalay 2007), in which affected family members were homozygou s for this variant. In addition, the variant is absent in 176 race matched chrom osomes (Ahmed 2008) and from large population studies. This variant is located i n the 5' splice region and functional studies have shown that the variant result s in exon-skipping and leads to a frameshift and a premature stop codon (Ahmed 2 008). Although these findings suggest that loss of function variants in LRTOMT a re causative for hearing loss, the exact mechanism of disease for LRTOMT related hearing loss has not been established. In summary, although additional studies are required to fully establish its clinical significance, this variant is likel y pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.030		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: rs545947177; hg19: chr11-71817260;