rs61741195

Variant names:

• chr11-72108672-G-A
• rs61741195
• NM_001393500.2:c.524G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-72108672-G-A
• chr11-72108672-G-T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 8 publications found

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: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]

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

Our verdict: Benign. The variant received -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 VariationId is 44040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	NM_001393500.2	MANE Select	c.524G>A	p.Arg175Gln	missense	Exon 3 of 3	NP_001380429.1
	LRTOMT	NM_001145308.5		c.623G>A	p.Arg208Gln	missense	Exon 7 of 7	NP_001138780.1
	LRTOMT	NM_001145309.4		c.623G>A	p.Arg208Gln	missense	Exon 9 of 9	NP_001138781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMT	ENST00000541899.3	TSL:5 MANE Select	c.524G>A	p.Arg175Gln	missense	Exon 3 of 3	ENSP00000494667.1
	LRTOMT	ENST00000307198.11	TSL:2	c.623G>A	p.Arg208Gln	missense	Exon 7 of 7	ENSP00000305742.7
	LRTOMT	ENST00000427369.6	TSL:1	n.*342G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000409403.2

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

GnomAD2 exomes AF: 0.00774 AC: 1094 AN: 141340 AF XY: 0.00820

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 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

African (AFR) AF: 0.00178 AC: 56 AN: 31440

American (AMR) AF: 0.00695 AC: 243 AN: 34962

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 241 AN: 23762

East Asian (EAS) AF: 0.00 AC: 0 AN: 35590

South Asian (SAS) AF: 0.00769 AC: 589 AN: 76628

European-Finnish (FIN) AF: 0.00203 AC: 96 AN: 47310

Middle Eastern (MID) AF: 0.00567 AC: 32 AN: 5642

European-Non Finnish (NFE) AF: 0.0137 AC: 14707 AN: 1070508

Other (OTH) AF: 0.0109 AC: 628 AN: 57398

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

African (AFR) AF: 0.00217 AC: 90 AN: 41542

American (AMR) AF: 0.0106 AC: 162 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 877 AN: 68012

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0112 Hom.: 38

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 63 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N
PhyloP100		0.32
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.020
Sift	Benign	0.31	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	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
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs61741195; hg19: chr11-71819718;