rs7130051

Variant names:

• chr11-17558503-A-C
• rs7130051
• NM_001292063.2:c.997-35A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.997-35A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,548,478 control chromosomes in the GnomAD database, including 20,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2556 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18198 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.273
• Publications: 5 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=-0.82).
• BP6: Variant 11-17558503-A-C is Benign according to our data. Variant chr11-17558503-A-C is described in ClinVar as Benign. ClinVar VariationId is 682654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

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.997-35A>C		intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.1033-35A>C		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.997-35A>C		intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.1033-35A>C		intron	N/A	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000485669.1	TSL:4	n.446A>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26397 AN: 152078 Hom.: 2557 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.134 AC: 19587 AN: 146074 AF XY: 0.134

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.000742

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.157 AC: 218604 AN: 1396282 Hom.: 18198 Cov.: 32 AF XY: 0.154 AC XY: 106321 AN XY: 688738

African (AFR) AF: 0.250 AC: 7906 AN: 31574

American (AMR) AF: 0.101 AC: 3595 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4796 AN: 25158

East Asian (EAS) AF: 0.00308 AC: 110 AN: 35722

South Asian (SAS) AF: 0.0988 AC: 7824 AN: 79178

European-Finnish (FIN) AF: 0.138 AC: 6617 AN: 47814

Middle Eastern (MID) AF: 0.209 AC: 1178 AN: 5632

European-Non Finnish (NFE) AF: 0.165 AC: 177276 AN: 1077552

Other (OTH) AF: 0.161 AC: 9302 AN: 57950

GnomAD4 genome AF: 0.174 AC: 26407 AN: 152196 Hom.: 2556 Cov.: 33 AF XY: 0.167 AC XY: 12456 AN XY: 74392

African (AFR) AF: 0.247 AC: 10266 AN: 41514

American (AMR) AF: 0.138 AC: 2116 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 661 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.0879 AC: 424 AN: 4822

European-Finnish (FIN) AF: 0.129 AC: 1366 AN: 10606

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11060 AN: 67994

Other (OTH) AF: 0.173 AC: 364 AN: 2108

Alfa AF: 0.165 Hom.: 1247

Bravo AF: 0.178

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.4
DANN	Benign	0.72
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7130051; hg19: chr11-17580050;