11-72104982-A-C

Variant names:

• chr11-72104982-A-C
• rs876657865
• ENST00000307198.11:c.53A>C

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.53A>C​(p.Asp18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: LRTOMT NM_001145308.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339

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]

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=0.053317994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRTOMT	NM_001145308.5	c.53A>C	p.Asp18Ala	missense_variant	Exon 4 of 7		NP_001138780.1
LRTOMT	NM_001145309.4	c.53A>C	p.Asp18Ala	missense_variant	Exon 6 of 9		NP_001138781.1
LRTOMT	NM_001145310.4	c.53A>C	p.Asp18Ala	missense_variant	Exon 6 of 9		NP_001138782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRTOMT	ENST00000307198.11	c.53A>C	p.Asp18Ala	missense_variant	Exon 4 of 7	2		ENSP00000305742.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000645 AC: 1 AN: 155126 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399318 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690168

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31596

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35698

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25180

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35736

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79224

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49284

Gnomad4 NFE exome AF: 0.00000371 AC: 4 AN: 1078898

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Asp18Ala vari ant in LRTOMT has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tools and conservation analyses suggest that the p.Asp18Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Asp18Ala variant is uncertain, these dat a suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.1
DANN	Benign	0.62
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.12	T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.072
Sift	Benign	0.54	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0	B;B
Vest4		0.077
MutPred		0.40		Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);
MVP		0.29
MPC		0.076
ClinPred		0.021	T
GERP RS		2.7
Varity_R		0.042
gMVP		0.44
Mutation Taster		=90/10	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657865; hg19: chr11-71816028;