11-72105937-G-C

Variant names:

• chr11-72105937-G-C
• rs748064285
• ENST00000307198.11:c.85G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145308.5(LRTOMT):​c.85G>C​(p.Ala29Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRTOMT NM_001145308.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002230
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325

Genes affected

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08584091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.-15G>C		5_prime_UTR_variant	Exon 1 of 3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145308.5	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	Exon 5 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	Exon 7 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.84-119G>C		intron_variant	Intron 6 of 8		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTOMT	ENST00000307198.11	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	Exon 5 of 7	2		ENSP00000305742.7
TOMT	ENST00000541899	c.-15G>C		5_prime_UTR_variant	Exon 1 of 3	5	NM_001393500.2	ENSP00000494667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	3.4
DANN	Benign	0.83
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.26	T;.
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.38	B;B
Vest4		0.27
MutPred		0.46		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.43
MPC		0.10
ClinPred		0.092	T
GERP RS		0.91
Varity_R		0.064
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs748064285; hg19: chr11-71816983; COSMIC: COSV105845966; COSMIC: COSV105845966;