chr11-72108672-G-A

Position:

• chr11-72108672-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001393500.2(TOMT):​c.524G>A​(p.Arg175Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,535,518 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (106 hom.)
• Consequence: TOMT NM_001393500.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.321

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:):

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003430903).
• BP6: Variant 11-72108672-G-A is Benign according to our data. Variant chr11-72108672-G-A is described in ClinVar as [Benign]. Clinvar id is 44040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72108672-G-A is described in Lovd as [Benign]. Variant chr11-72108672-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0084 (1279/152278) while in subpopulation NFE AF= 0.0129 (877/68012). AF 95% confidence interval is 0.0122. There are 6 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMT	NM_001393500.2	c.524G>A	p.Arg175Gln	missense_variant	3/3	ENST00000541899.3	NP_001380429.1
LRTOMT	NM_001145309.4	c.623G>A	p.Arg208Gln	missense_variant	9/9		NP_001138781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMT	ENST00000541899.3	c.524G>A	p.Arg175Gln	missense_variant	3/3	5	NM_001393500.2	ENSP00000494667	P1
ANAPC15	ENST00000502597.2	c.64-1067C>T		intron_variant		1		ENSP00000441774
ANAPC15	ENST00000543050.5	c.319-1067C>T		intron_variant		3		ENSP00000437360

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1278 AN: 152158 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00774 AC: 1094 AN: 141340 Hom.: 7 AF XY: 0.00820 AC XY: 610 AN XY: 74424

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.00924

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00723

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00922

GnomAD4 exome AF: 0.0120 AC: 16592 AN: 1383240 Hom.: 106 Cov.: 32 AF XY: 0.0118 AC XY: 8000 AN XY: 680676

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00769

Gnomad4 FIN exome AF: 0.00203

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152278 Hom.: 6 Cov.: 32 AF XY: 0.00800 AC XY: 596 AN XY: 74470

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0105 Hom.: 19

Bravo AF: 0.00866

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00880 AC: 28

ExAC AF: 0.00564 AC: 152

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2018	This variant is associated with the following publications: (PMID: 27884173, 18794526, 30245029) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ANAPC15: BS1, BS2; LRTOMT: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg208Gln in Exon 07 of LRTOMT: This variant is not expected to have clinical si gnificance because it has been identified in 0.9% (23/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61741195). -

Autosomal recessive nonsyndromic hearing loss 63 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.065	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T;.;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;N;.
REVEL	Benign	0.020
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.59	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.032
MVP		0.48
MPC		0.073
ClinPred		0.0048	T
GERP RS		-0.17
Varity_R		0.059
gMVP		0.23

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: rs61741195; hg19: chr11-71819718;