rs55881341

Variant names:

• chr11-17578506-G-A
• rs55881341
• NM_001292063.2:c.2739G>A

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.2739G>A​(p.Ser913Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,537,564 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.589
• Publications: 0 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 11-17578506-G-A is Benign according to our data. Variant chr11-17578506-G-A is described in ClinVar as Benign. ClinVar VariationId is 226875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1740/152334) while in subpopulation AFR AF = 0.0393 (1635/41584). AF 95% confidence interval is 0.0377. There are 27 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.2739G>A	p.Ser913Ser	synonymous	Exon 23 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.2775G>A	p.Ser925Ser	synonymous	Exon 22 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.2739G>A	p.Ser913Ser	synonymous	Exon 23 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.2775G>A	p.Ser925Ser	synonymous	Exon 22 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.243G>A		non_coding_transcript_exon	Exon 1 of 22

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1734 AN: 152216 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00239 AC: 328 AN: 137092 AF XY: 0.00185

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000265

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00112 AC: 1551 AN: 1385230 Hom.: 26 Cov.: 32 AF XY: 0.00100 AC XY: 685 AN XY: 683556

African (AFR) AF: 0.0386 AC: 1218 AN: 31560

American (AMR) AF: 0.00245 AC: 87 AN: 35494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.000139 AC: 11 AN: 78996

European-Finnish (FIN) AF: 0.000574 AC: 21 AN: 36578

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5680

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1078274

Other (OTH) AF: 0.00316 AC: 183 AN: 57844

GnomAD4 genome AF: 0.0114 AC: 1740 AN: 152334 Hom.: 27 Cov.: 33 AF XY: 0.0109 AC XY: 814 AN XY: 74490

African (AFR) AF: 0.0393 AC: 1635 AN: 41584

American (AMR) AF: 0.00523 AC: 80 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00649 Hom.: 0

Bravo AF: 0.0128

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.2
DANN	Benign	0.84
PhyloP100		-0.59
Mutation Taster		=296/4	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: rs55881341; hg19: chr11-17600053;