rs143393149

Variant names:

• chr11-17596943-C-T
• rs143393149
• NM_001292063.2:c.3618C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.3618C>T​(p.Ser1206Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,550,718 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.19
• Publications: 3 publications found

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-17596943-C-T is Benign according to our data. Variant chr11-17596943-C-T is described in ClinVar as Benign. ClinVar VariationId is 226889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00243 (370/152294) while in subpopulation EAS AF = 0.0512 (265/5178). AF 95% confidence interval is 0.0461. There are 6 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.3618C>T	p.Ser1206Ser	synonymous	Exon 30 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3654C>T	p.Ser1218Ser	synonymous	Exon 29 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.3618C>T	p.Ser1206Ser	synonymous	Exon 30 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.3654C>T	p.Ser1218Ser	synonymous	Exon 29 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.983C>T		non_coding_transcript_exon	Exon 7 of 22

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152176 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00458 AC: 685 AN: 149724 AF XY: 0.00449

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00128 AC: 1791 AN: 1398424 Hom.: 26 Cov.: 31 AF XY: 0.00126 AC XY: 868 AN XY: 689736

African (AFR) AF: 0.000601 AC: 19 AN: 31600

American (AMR) AF: 0.000252 AC: 9 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000794 AC: 2 AN: 25182

East Asian (EAS) AF: 0.0350 AC: 1251 AN: 35736

South Asian (SAS) AF: 0.00170 AC: 135 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000639 AC: 69 AN: 1079004

Other (OTH) AF: 0.00527 AC: 306 AN: 58036

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152294 Hom.: 6 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74460

African (AFR) AF: 0.00120 AC: 50 AN: 41568

American (AMR) AF: 0.00124 AC: 19 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5178

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4816

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000556 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.2
DANN	Benign	0.77
PhyloP100		-2.2
Mutation Taster		=95/5	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: rs143393149; hg19: chr11-17618490; COSMIC: COSV61133551;