rs17686437

chr20-16748403-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The NM_020157.4(OTOR):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0392 in 1,602,702 control chromosomes in the GnomAD database, including 1,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (101 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1294 hom.)
• Consequence: OTOR NM_020157.4 start_lost
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.17

Genes affected

OTOR (HGNC:8517): (otoraplin) This gene encodes a member of the melanoma-inhibiting activity gene family. The encoded protein is secreted via the Golgi apparatus and may function in cartilage development and maintenance. A frequent polymorphism in the translation start codon of this gene can abolish translation and may be associated with forms of deafness. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 20-16748403-T-C is Benign according to our data. Variant chr20-16748403-T-C is described in ClinVar as [Benign]. Clinvar id is 403282.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-16748403-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0319 (4852/152252) while in subpopulation NFE AF= 0.0447 (3037/68012). AF 95% confidence interval is 0.0433. There are 101 homozygotes in gnomad4. There are 2409 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 101 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOR	NM_020157.4	c.2T>C	p.Met1?	start_lost	1/4	ENST00000246081.3
OTOR	XM_017027959.3	c.2T>C	p.Met1?	start_lost	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOR	ENST00000246081.3	c.2T>C	p.Met1?	start_lost	1/4	1	NM_020157.4	P1

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4854 AN: 152134 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0358

GnomAD3 exomes AF: 0.0348 AC: 8743 AN: 251144 Hom.: 191 AF XY: 0.0358 AC XY: 4857 AN XY: 135716

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0249

Gnomad FIN exome AF: 0.0540

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0340

GnomAD4 exome AF: 0.0399 AC: 57945 AN: 1450450 Hom.: 1294 Cov.: 28 AF XY: 0.0403 AC XY: 29086 AN XY: 722410

Gnomad4 AFR exome AF: 0.00734

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0636

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0246

Gnomad4 FIN exome AF: 0.0518

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0319 AC: 4852 AN: 152252 Hom.: 101 Cov.: 32 AF XY: 0.0324 AC XY: 2409 AN XY: 74454

Gnomad4 AFR AF: 0.00859

Gnomad4 AMR AF: 0.0287

Gnomad4 ASJ AF: 0.0625

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0513

Gnomad4 NFE AF: 0.0447

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0429 Hom.: 308

Bravo AF: 0.0283

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0453 AC: 390

ExAC AF: 0.0352 AC: 4269

Asia WGS AF: 0.0120 AC: 41 AN: 3476

EpiCase AF: 0.0497

EpiControl AF: 0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all):430/13006=3.3% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	P
Vest4		0.34
ClinPred		0.037	T
GERP RS		5.9
Varity_R		0.66
gMVP		0.83

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: rs17686437; hg19: chr20-16729048;