rs545542156

Variant names:

• chr11-17635201-A-T
• rs545542156
• NM_001292063.2:c.7693+14A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.7693+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,528,748 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.47
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-17635201-A-T is Benign according to our data. Variant chr11-17635201-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227798.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 = 0.00197 (299/151436) while in subpopulation NFE AF = 0.00303 (205/67752). AF 95% confidence interval is 0.00269. There are 1 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.7693+14A>T		intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.7729+14A>T		intron	N/A	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.7693+14A>T		intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.7729+14A>T		intron	N/A	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.4606-409A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 299 AN: 151318 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00332

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00166 AC: 219 AN: 132164 AF XY: 0.00159

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00317

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00268 AC: 3698 AN: 1377312 Hom.: 9 Cov.: 31 AF XY: 0.00268 AC XY: 1822 AN XY: 679546

African (AFR) AF: 0.000416 AC: 13 AN: 31260

American (AMR) AF: 0.00157 AC: 55 AN: 35124

Ashkenazi Jewish (ASJ) AF: 0.000806 AC: 20 AN: 24802

East Asian (EAS) AF: 0.00 AC: 0 AN: 35664

South Asian (SAS) AF: 0.000114 AC: 9 AN: 78680

European-Finnish (FIN) AF: 0.00365 AC: 139 AN: 38070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 0.00315 AC: 3377 AN: 1070858

Other (OTH) AF: 0.00148 AC: 85 AN: 57450

GnomAD4 genome AF: 0.00197 AC: 299 AN: 151436 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 153 AN XY: 73972

African (AFR) AF: 0.000776 AC: 32 AN: 41228

American (AMR) AF: 0.00157 AC: 24 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00332 AC: 35 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00303 AC: 205 AN: 67752

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00180

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.014
DANN	Benign	0.42
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs545542156; hg19: chr11-17656748;