Genetic Variant NM_001393500.2:c.439_441delGGCinsTCT (chr11-72108102-GGC-TCT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001393500.2(TOMT):c.439_441delGGCinsTCT (p.Gly147Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.25). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G147S: Uncertain_significance (ClinVar VariationId 587638, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

TOMT
NM_001393500.2 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.25

Publications

0 publications found

Variant links:

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]

TOMT links:

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

LRTOMT links:

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]

ANAPC15 links:

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new If you want to explore the variant's impact on the transcript NM_001393500.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TOMT NM_001393500.2	MANE Select	c.439_441delGGCinsTCT p.Gly147Ser	missense	N/A	Prot: NP_001380429.1 UniProt: A0A2R8Y5M8
LRTOMT NM_001145308.5		c.538_540delGGCinsTCT p.Gly180Ser	missense	N/A	Prot: NP_001138780.1
LRTOMT NM_001145309.4		c.538_540delGGCinsTCT p.Gly180Ser	missense	N/A	Prot: NP_001138781.1

TOMT NM_001393500.2

MANE Select

HGVSc / HGVSpc.439_441delGGCinsTCTp.Gly147Ser

Exon rankN/A

missense

Prot: NP_001380429.1UniProt: A0A2R8Y5M8

LRTOMT NM_001145308.5

HGVSc / HGVSpc.538_540delGGCinsTCTp.Gly180Ser

Exon rankN/A

missense

Prot: NP_001138780.1

LRTOMT NM_001145309.4

HGVSc / HGVSpc.538_540delGGCinsTCTp.Gly180Ser

Exon rankN/A

missense

Prot: NP_001138781.1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TOMT ENST00000541899.3	TSL:5MANE Select	c.439_441delGGCinsTCT p.Gly147Ser	missense	N/A	Prot: ENSP00000494667.1 UniProt: A0A2R8Y5M8
LRTOMT ENST00000307198.11	TSL:2	c.538_540delGGCinsTCT p.Gly180Ser	missense	N/A	Prot: ENSP00000305742.7 UniProt: Q8WZ04-1
ANAPC15 ENST00000502597.2	TSL:1	c.64-499_64-497delGCCinsAGA	intron	Intron 3 of 3	Prot: ENSP00000441774.1 UniProt: F5GWM6

TOMT ENST00000541899.3

TSL:5MANE Select

HGVSc / HGVSpc.439_441delGGCinsTCTp.Gly147Ser

Exon rankN/A

missense

Prot: ENSP00000494667.1UniProt: A0A2R8Y5M8

LRTOMT ENST00000307198.11

TSL:2

HGVSc / HGVSpc.538_540delGGCinsTCTp.Gly180Ser

Exon rankN/A

missense

Prot: ENSP00000305742.7UniProt: Q8WZ04-1

ANAPC15 ENST00000502597.2

TSL:1

HGVSc / HGVSpc.64-499_64-497delGCCinsAGA

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence