rs4757548

Variant names:

• chr11-17574766-G-A
• rs4757548
• NM_001292063.2:c.2340G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17574766-G-A
• chr11-17574766-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001277269.2(OTOG):​c.2376G>A​(p.Pro792Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,550,218 control chromosomes in the GnomAD database, including 116,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P792P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (10621 hom., cov: 33)
  • Exomes 𝑓: 0.39 (105942 hom.)
• Consequence: OTOG NM_001277269.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.372
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-17574766-G-A is Benign according to our data. Variant chr11-17574766-G-A is described in ClinVar as Benign. ClinVar VariationId is 226868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.372 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 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.2340G>A	p.Pro780Pro	synonymous	Exon 20 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.2376G>A	p.Pro792Pro	synonymous	Exon 19 of 55	NP_001264198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2340G>A	p.Pro780Pro	synonymous	Exon 20 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.2376G>A	p.Pro792Pro	synonymous	Exon 19 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56197 AN: 152040 Hom.: 10617 Cov.: 33

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.337 AC: 50313 AN: 149100 AF XY: 0.342

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.387 AC: 540406 AN: 1398060 Hom.: 105942 Cov.: 50 AF XY: 0.385 AC XY: 265506 AN XY: 689526

African (AFR) AF: 0.369 AC: 11648 AN: 31580

American (AMR) AF: 0.208 AC: 7404 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 9663 AN: 25156

East Asian (EAS) AF: 0.228 AC: 8136 AN: 35718

South Asian (SAS) AF: 0.316 AC: 25059 AN: 79196

European-Finnish (FIN) AF: 0.378 AC: 18242 AN: 48226

Middle Eastern (MID) AF: 0.352 AC: 2004 AN: 5696

European-Non Finnish (NFE) AF: 0.404 AC: 436354 AN: 1078838

Other (OTH) AF: 0.378 AC: 21896 AN: 57984

GnomAD4 genome AF: 0.370 AC: 56224 AN: 152158 Hom.: 10621 Cov.: 33 AF XY: 0.366 AC XY: 27196 AN XY: 74368

African (AFR) AF: 0.375 AC: 15555 AN: 41520

American (AMR) AF: 0.265 AC: 4050 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1322 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1376 AN: 5172

South Asian (SAS) AF: 0.309 AC: 1492 AN: 4828

European-Finnish (FIN) AF: 0.378 AC: 4006 AN: 10586

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27167 AN: 67970

Other (OTH) AF: 0.349 AC: 735 AN: 2108

Alfa AF: 0.391 Hom.: 21905

Bravo AF: 0.360

Asia WGS AF: 0.307 AC: 1068 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	Autosomal recessive nonsyndromic hearing loss 18B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		-0.37
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4757548; hg19: chr11-17596313; COSMIC: COSV61128395; COSMIC: COSV61128395;