11-72105937-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145308.5(LRTOMT):​c.85G>T​(p.Ala29Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A29T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LRTOMT NM_001145308.5 missense, splice_region
• Scores: Splicing: ADA: 0.000007402
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056471437).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 3	NP_001380429.1	A0A2R8Y5M8
	LRTOMT	NM_001145308.5		c.85G>T	p.Ala29Ser	missense splice_region	Exon 5 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.85G>T	p.Ala29Ser	missense splice_region	Exon 7 of 9	NP_001138781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRTOMT	ENST00000307198.11	TSL:2	c.85G>T	p.Ala29Ser	missense splice_region	Exon 5 of 7	ENSP00000305742.7
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 3	ENSP00000494667.1	A0A2R8Y5M8
	LRTOMT	ENST00000427369.6	TSL:1	n.488G>T		splice_region non_coding_transcript_exon	Exon 7 of 9	ENSP00000409403.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385364 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 680528

⚠️ 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: 31328

American (AMR) AF: 0.00 AC: 0 AN: 35522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25002

East Asian (EAS) AF: 0.00 AC: 0 AN: 35398

South Asian (SAS) AF: 0.00 AC: 0 AN: 78954

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4182

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068852

Other (OTH) AF: 0.00 AC: 0 AN: 57236

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.4
DANN	Benign	0.70
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.33
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.25
Sift	Benign	0.42	T
Sift4G	Benign	0.68	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.36		Loss of helix (P = 0.0068)
MVP		0.45
MPC		0.061
ClinPred		0.057	T
GERP RS		0.91
PromoterAI		0.00020	Neutral
Varity_R		0.030
gMVP		0.097
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000074
dbscSNV1_RF	Benign	0.0
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: rs748064285; hg19: chr11-71816983;