11-17576544-AT-ATT

Variant names:

• chr11-17576544-A-AT
• rs562652501
• NM_001292063.2:c.2487-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.2487-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,548,720 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (5 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.851
• 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 -16 ACMG points.

• BP6: Variant 11-17576544-A-AT is Benign according to our data. Variant chr11-17576544-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 506217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000132 (20/152028) while in subpopulation SAS AF = 0.00354 (17/4796). AF 95% confidence interval is 0.00226. There are 2 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2487-5dupT		splice_region intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.2523-5dupT		splice_region 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.2487-12_2487-11insT		intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.2523-12_2523-11insT		intron	N/A	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151910 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000496 AC: 74 AN: 149066 AF XY: 0.000635

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000191 AC: 267 AN: 1396692 Hom.: 5 Cov.: 30 AF XY: 0.000284 AC XY: 196 AN XY: 688986

African (AFR) AF: 0.0000951 AC: 3 AN: 31550

American (AMR) AF: 0.0000280 AC: 1 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35730

South Asian (SAS) AF: 0.00307 AC: 243 AN: 79204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48174

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.00000928 AC: 10 AN: 1077506

Other (OTH) AF: 0.000104 AC: 6 AN: 57954

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152028 Hom.: 2 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00354 AC: 17 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.85
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: rs562652501; hg19: chr11-17598091;