rs11024353

Variant names:

• chr11-17638557-C-T
• rs11024353
• NM_001292063.2:c.7894+8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.7894+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,549,324 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (139 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1298 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004638
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27
• Publications: 2 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), PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-17638557-C-T is Benign according to our data. Variant chr11-17638557-C-T is described in ClinVar as Benign. ClinVar VariationId is 226912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

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.7894+8C>T		splice_region intron	N/A	NP_001278992.1
	OTOG	NM_001277269.2		c.7930+8C>T		splice_region intron	N/A	NP_001264198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7894+8C>T		splice_region intron	N/A	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7930+8C>T		splice_region intron	N/A	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4806+8C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6041 AN: 152078 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0442 AC: 6542 AN: 147882 AF XY: 0.0462

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0540

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0401 AC: 56050 AN: 1397126 Hom.: 1298 Cov.: 30 AF XY: 0.0413 AC XY: 28459 AN XY: 689126

African (AFR) AF: 0.0394 AC: 1244 AN: 31588

American (AMR) AF: 0.0424 AC: 1511 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 644 AN: 25150

East Asian (EAS) AF: 0.0432 AC: 1543 AN: 35732

South Asian (SAS) AF: 0.0828 AC: 6558 AN: 79184

European-Finnish (FIN) AF: 0.0311 AC: 1491 AN: 48018

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5690

European-Non Finnish (NFE) AF: 0.0379 AC: 40874 AN: 1078142

Other (OTH) AF: 0.0365 AC: 2116 AN: 57952

GnomAD4 genome AF: 0.0398 AC: 6051 AN: 152198 Hom.: 139 Cov.: 32 AF XY: 0.0418 AC XY: 3107 AN XY: 74406

African (AFR) AF: 0.0400 AC: 1662 AN: 41512

American (AMR) AF: 0.0525 AC: 804 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.0530 AC: 274 AN: 5170

South Asian (SAS) AF: 0.0871 AC: 420 AN: 4820

European-Finnish (FIN) AF: 0.0349 AC: 370 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0346 AC: 2352 AN: 67998

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0349 Hom.: 42

Bravo AF: 0.0377

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.78
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs11024353; hg19: chr11-17660104;