rs876657864

Positions:

• chr11-72106048-C-A
• chr11-72106048-C-G
• chr11-72106048-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001393500.2(TOMT):​c.97C>A​(p.Leu33Met) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. 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. L33V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26846084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMT	NM_001393500.2	c.97C>A	p.Leu33Met	missense_variant	1/3	ENST00000541899.3
LRTOMT	NM_001145309.4	c.196C>A	p.Leu66Met	missense_variant	7/9
LRTOMT	NM_001145308.5	c.196C>A	p.Leu66Met	missense_variant	5/7
LRTOMT	NM_001145310.4	c.84-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMT	ENST00000541899.3	c.97C>A	p.Leu33Met	missense_variant	1/3	5	NM_001393500.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.51	T;.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.19	N;N;.
REVEL	Benign	0.23
Sift	Benign	0.051	T;T;.
Sift4G	Benign	0.14	T;T;.
Polyphen		0.0060	B;B;.
Vest4		0.23
MutPred		0.37		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);.;
MVP		0.58
MPC		0.26
ClinPred		0.82	D
GERP RS		3.5
Varity_R		0.072
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657864; hg19: chr11-71817094;