rs529549122

Variant names:

• chr11-72108102-G-A
• rs529549122
• NM_001393500.2:c.439G>A
• TOMT p.Gly147Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM2PP3_Moderate

The NM_001393500.2(TOMT):c.439G>A (p.Gly147Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000021 (AC=32) in the gnomAD database across 1,523,286 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000238. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.25). Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25
• Publications: 0 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]

LRTOMT Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 63

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ANAPC15 (HGNC:24531): (anaphase promoting complex subunit 15) Involved in anaphase-promoting complex-dependent catabolic process; protein polyubiquitination; and regulation of mitotic cell cycle spindle assembly checkpoint. Part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Jul 2025]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000238 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOMT NM_001393500.2	MANE Select	c.439G>A p.Gly147Ser	missense	Exon 2 of 3	Prot: NP_001380429.1 UniProt:
	LRTOMT NM_001145308.5		c.538G>A p.Gly180Ser	missense	Exon 6 of 7	Prot: NP_001138780.1
	LRTOMT NM_001145309.4		c.538G>A p.Gly180Ser	missense	Exon 8 of 9	Prot: NP_001138781.1

TOMT NM_001393500.2

MANE Select

HGVSc / HGVSpc.439G>Ap.Gly147Ser

Exon rankExon 2 of 3

missense

Prot: NP_001380429.1UniProt: A0A2R8Y5M8

LRTOMT NM_001145308.5

HGVSc / HGVSpc.538G>Ap.Gly180Ser

Exon rankExon 6 of 7

missense

Prot: NP_001138780.1

LRTOMT NM_001145309.4

HGVSc / HGVSpc.538G>Ap.Gly180Ser

Exon rankExon 8 of 9

missense

Prot: NP_001138781.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TOMT ENST00000541899.3	TSL:5MANE Select	c.439G>A p.Gly147Ser	missense	Exon 2 of 3	Prot: ENSP00000494667.1 UniProt:
	LRTOMT ENST00000307198.11	TSL:2	c.538G>A p.Gly180Ser	missense	Exon 6 of 7	Prot: ENSP00000305742.7 UniProt:
	ANAPC15 ENST00000502597.2	TSL:1	c.64-497C>T	intron	Intron 3 of 3	Prot: ENSP00000441774.1 UniProt:

TOMT ENST00000541899.3

TSL:5MANE Select

HGVSc / HGVSpc.439G>Ap.Gly147Ser

Exon rankExon 2 of 3

missense

Prot: ENSP00000494667.1UniProt: A0A2R8Y5M8

LRTOMT ENST00000307198.11

TSL:2

HGVSc / HGVSpc.538G>Ap.Gly180Ser

Exon rankExon 6 of 7

missense

Prot: ENSP00000305742.7UniProt: Q8WZ04-1

ANAPC15 ENST00000502597.2

TSL:1

HGVSc / HGVSpc.64-497C>T

Exon rankIntron 3 of 3

intron

Prot: ENSP00000441774.1UniProt: F5GWM6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152132	Cov:32
GnomAD2 exomes	AF: 0.0000520	AC:7	Hom:	AN:134688	Cov:
GnomAD4 exome	AF: 0.0000197	AC:27	Hom:0	AN:1371036	Cov:31
GnomAD4 genome	AF: 0.0000328	AC:5	Hom:0	AN:152250	Cov:32
TOPMed (Bravo)	AF: 0.0000718	AC:19	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000451	AC:1	Hom:0	AN:22150	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
Korea4K (4,157 Koreans)	AF: 0.000553	AC:4	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122354	Cov:
Turkish Variome	AF: 0.000453	AC:3	Hom:0	AN:6626	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000239	1	41762	0.0000457	3	65710
SCHEMA(Schizophrenia)	0.000471	49	103970	0.000496	83	167188

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 63 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.96
GPN-Star LLR	N/A	-5.7
GPN-Star score	N/A	5.7
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.60	D
Mutation Taster	N/A	29/71	disease causing
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Pathogenic	9.3
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.89
VESM-3B	Benign	-8.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs529549122;

hg19: chr11-71819148;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar