rs11024331

Variant names:

• chr11-17591549-G-A
• rs11024331
• NM_001292063.2:c.2967G>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.2967G>A​(p.Pro989Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,550,632 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.58
• Publications: 1 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=-0.72).
• BP6: Variant 11-17591549-G-A is Benign according to our data. Variant chr11-17591549-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00358 (545/152332) while in subpopulation AFR AF = 0.0123 (513/41580). AF 95% confidence interval is 0.0115. There are 4 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.2967G>A	p.Pro989Pro	synonymous	Exon 25 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3003G>A	p.Pro1001Pro	synonymous	Exon 24 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.2967G>A	p.Pro989Pro	synonymous	Exon 25 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.3003G>A	p.Pro1001Pro	synonymous	Exon 24 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.372-1644G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 541 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000724 AC: 108 AN: 149194 AF XY: 0.000697

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000927

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000463

GnomAD4 exome AF: 0.000352 AC: 492 AN: 1398300 Hom.: 2 Cov.: 32 AF XY: 0.000296 AC XY: 204 AN XY: 689674

African (AFR) AF: 0.0128 AC: 405 AN: 31596

American (AMR) AF: 0.000980 AC: 35 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48166

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078982

Other (OTH) AF: 0.000603 AC: 35 AN: 57998

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00341 AC XY: 254 AN XY: 74484

African (AFR) AF: 0.0123 AC: 513 AN: 41580

American (AMR) AF: 0.00163 AC: 25 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00403

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.76
PhyloP100		-3.6
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11024331; hg19: chr11-17613096;