rs141597314

chr11-17552085-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):c.292+10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,549,972 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., cov: 33)
  • Exomes 𝑓: 0.018 (272 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.72

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-17552085-A-T is Benign according to our data. Variant chr11-17552085-A-T is described in ClinVar as [Benign]. Clinvar id is 226881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2186/152246) while in subpopulation NFE AF= 0.0205 (1395/67986). AF 95% confidence interval is 0.0196. There are 28 homozygotes in gnomad4. There are 1099 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.292+10A>T		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.328+10A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.292+10A>T		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.328+10A>T		intron_variant		5		A2
OTOG	ENST00000428619.1	c.109+10A>T		intron_variant		3
OTOG	ENST00000498332.5	n.198+10A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152128 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0140 AC: 2086 AN: 149136 Hom.: 23 AF XY: 0.0137 AC XY: 1100 AN XY: 80322

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00965

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00564

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0184 AC: 25670 AN: 1397726 Hom.: 272 Cov.: 30 AF XY: 0.0180 AC XY: 12408 AN XY: 689452

Gnomad4 AFR exome AF: 0.00301

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00583

Gnomad4 FIN exome AF: 0.0232

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0144 AC: 2186 AN: 152246 Hom.: 28 Cov.: 33 AF XY: 0.0148 AC XY: 1099 AN XY: 74452

Gnomad4 AFR AF: 0.00414

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0159 Hom.: 6

Bravo AF: 0.0132

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	328+10A>T in intron 3 of OTOG: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 4.2% (5/120) of Colombian chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/projects/SN P; dbSNP rs141597314). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.3
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs141597314; hg19: chr11-17573632;