rs17686437

Variant names:

• chr20-16748403-T-C
• rs17686437
• NM_020157.4:c.2T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.17
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 23 codons. Genomic position: 16748468. Lost 0.173 part of the original CDS.
• BP6: Variant 20-16748403-T-C is Benign according to our data. Variant chr20-16748403-T-C is described in ClinVar as Benign. ClinVar VariationId is 403282.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 = 0.0319 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 101 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020157.4. 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
	OTOR	NM_020157.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 4	NP_064542.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOR	ENST00000246081.3	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 4	ENSP00000246081.3

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

GnomAD2 exomes AF: 0.0348 AC: 8743 AN: 251144 AF XY: 0.0358

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 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

African (AFR) AF: 0.00734 AC: 244 AN: 33244

American (AMR) AF: 0.0169 AC: 753 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1658 AN: 26050

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39622

South Asian (SAS) AF: 0.0246 AC: 2116 AN: 86028

European-Finnish (FIN) AF: 0.0518 AC: 2767 AN: 53392

Middle Eastern (MID) AF: 0.0443 AC: 254 AN: 5740

European-Non Finnish (NFE) AF: 0.0435 AC: 47906 AN: 1101738

Other (OTH) AF: 0.0374 AC: 2243 AN: 59948

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

African (AFR) AF: 0.00859 AC: 357 AN: 41550

American (AMR) AF: 0.0287 AC: 439 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 217 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4818

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0447 AC: 3037 AN: 68012

Other (OTH) AF: 0.0354 AC: 75 AN: 2116

Alfa AF: 0.0411 Hom.: 550

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.2
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
PromoterAI		0.044	Neutral
Varity_R		0.66
gMVP		0.83
Mutation Taster		=134/66	polymorphism (auto)

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: rs17686437; hg19: chr20-16729048; COSMIC: COSV107204647; COSMIC: COSV107204647;