rs4756901

Variant names:

• chr11-17576640-G-A
• rs4756901
• NM_001292063.2:c.2561+10G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17576640-G-A
• chr11-17576640-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001277269.2(OTOG):​c.2597+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,539,546 control chromosomes in the GnomAD database, including 111,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8830 hom., cov: 32)
  • Exomes 𝑓: 0.38 (102227 hom.)
• Consequence: OTOG NM_001277269.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00100
• Publications: 9 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 -16 ACMG points.

• BP6: Variant 11-17576640-G-A is Benign according to our data. Variant chr11-17576640-G-A is described in ClinVar as Benign. ClinVar VariationId is 226870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277269.2. 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.2561+10G>A		intron	N/A	NP_001278992.1
	OTOG	NM_001277269.2		c.2597+10G>A		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.2561+10G>A		intron	N/A	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.2597+10G>A		intron	N/A	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50431 AN: 151644 Hom.: 8831 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.330 AC: 49242 AN: 149210 AF XY: 0.336

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.380 AC: 527086 AN: 1387784 Hom.: 102227 Cov.: 32 AF XY: 0.379 AC XY: 259558 AN XY: 685080

African (AFR) AF: 0.250 AC: 7853 AN: 31422

American (AMR) AF: 0.197 AC: 7046 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9584 AN: 25130

East Asian (EAS) AF: 0.249 AC: 8868 AN: 35682

South Asian (SAS) AF: 0.316 AC: 25012 AN: 79068

European-Finnish (FIN) AF: 0.374 AC: 18012 AN: 48152

Middle Eastern (MID) AF: 0.339 AC: 1922 AN: 5670

European-Non Finnish (NFE) AF: 0.400 AC: 427714 AN: 1069308

Other (OTH) AF: 0.365 AC: 21075 AN: 57666

GnomAD4 genome AF: 0.332 AC: 50436 AN: 151762 Hom.: 8830 Cov.: 32 AF XY: 0.329 AC XY: 24425 AN XY: 74164

African (AFR) AF: 0.255 AC: 10544 AN: 41422

American (AMR) AF: 0.246 AC: 3765 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1312 AN: 3466

East Asian (EAS) AF: 0.276 AC: 1419 AN: 5146

South Asian (SAS) AF: 0.306 AC: 1473 AN: 4808

European-Finnish (FIN) AF: 0.373 AC: 3929 AN: 10534

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.395 AC: 26819 AN: 67812

Other (OTH) AF: 0.320 AC: 675 AN: 2108

Alfa AF: 0.333 Hom.: 3101

Bravo AF: 0.319

Asia WGS AF: 0.298 AC: 1039 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.56
PhyloP100		0.0010
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4756901; hg19: chr11-17598187; COSMIC: COSV61128336; COSMIC: COSV61128336;