11-72106180-G-C

Variant names:

• chr11-72106180-G-C
• rs137853187
• NM_001393500.2:c.229G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001145308.5(LRTOMT):​c.328G>C​(p.Glu110Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,361,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E110K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LRTOMT NM_001145308.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84
• 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]

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-72106180-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 545.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145308.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.229G>C	p.Glu77Gln	missense	Exon 1 of 3	NP_001380429.1
	LRTOMT	NM_001145308.5		c.328G>C	p.Glu110Gln	missense	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.328G>C	p.Glu110Gln	missense	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.229G>C	p.Glu77Gln	missense	Exon 1 of 3	ENSP00000494667.1
	LRTOMT	ENST00000307198.11	TSL:2	c.328G>C	p.Glu110Gln	missense	Exon 5 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.*47G>C		non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1361370 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 666442

African (AFR) AF: 0.00 AC: 0 AN: 31126

American (AMR) AF: 0.00 AC: 0 AN: 34702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35128

South Asian (SAS) AF: 0.00 AC: 0 AN: 77572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058320

Other (OTH) AF: 0.00 AC: 0 AN: 56618

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	2.0	M
PhyloP100		8.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.60		Loss of phosphorylation at Y111 (P = 0.1453)
MVP		0.86
MPC		0.39
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.033	Neutral
Varity_R		0.43
gMVP		0.70
Mutation Taster		=8/92	disease causing

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: rs137853187; hg19: chr11-71817226;