chr11-72108672-G-T

Variant names:

• chr11-72108672-G-T
• rs61741195
• NM_001393500.2:c.524G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393500.2(TOMT):​c.524G>T​(p.Arg175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,535,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R175Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321
• Publications: 8 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]

ANAPC15 (HGNC:24531): (anaphase promoting complex subunit 15) Involved in regulation of mitotic cell cycle spindle assembly checkpoint. Part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13607034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.524G>T	p.Arg175Leu	missense	Exon 3 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.623G>T	p.Arg208Leu	missense	Exon 7 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.623G>T	p.Arg208Leu	missense	Exon 9 of 9	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.524G>T	p.Arg175Leu	missense	Exon 3 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000307198.11	TSL:2	c.623G>T	p.Arg208Leu	missense	Exon 7 of 7	ENSP00000305742.7
	ANAPC15	ENST00000502597.2	TSL:1	c.64-1067C>A		intron	N/A	ENSP00000441774.1	F5GWM6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383254 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 680680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31440

American (AMR) AF: 0.00 AC: 0 AN: 34962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23764

East Asian (EAS) AF: 0.00 AC: 0 AN: 35590

South Asian (SAS) AF: 0.00 AC: 0 AN: 76630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070518

Other (OTH) AF: 0.0000174 AC: 1 AN: 57398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 38

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.32
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.082
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.10	B
Vest4		0.28
MutPred		0.45		Gain of sheet (P = 0.0827)
MVP		0.31
MPC		0.16
ClinPred		0.16	T
GERP RS		-0.17
Varity_R		0.25
gMVP		0.47
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61741195; hg19: chr11-71819718;