rs116503251

chr11-17631764-G-A

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.6775G>A(p.Ala2259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,550,604 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (17 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.577

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 (MetaRNN=0.0035794675).
• BP6: Variant 11-17631764-G-A is Benign according to our data. Variant chr11-17631764-G-A is described in ClinVar as [Benign]. Clinvar id is 226904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00766 (1167/152308) while in subpopulation AFR AF= 0.0269 (1118/41564). AF 95% confidence interval is 0.0256. There are 15 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6775G>A	p.Ala2259Thr	missense_variant	41/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6811G>A	p.Ala2271Thr	missense_variant	40/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6775G>A	p.Ala2259Thr	missense_variant	41/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6811G>A	p.Ala2271Thr	missense_variant	40/55	5		A2
OTOG	ENST00000342528.2	n.4113G>A		non_coding_transcript_exon_variant	17/22	2

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152190 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00147 AC: 219 AN: 149094 Hom.: 3 AF XY: 0.00113 AC XY: 91 AN XY: 80294

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.000936

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000695

GnomAD4 exome AF: 0.000805 AC: 1126 AN: 1398296 Hom.: 17 Cov.: 32 AF XY: 0.000687 AC XY: 474 AN XY: 689670

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00766 AC: 1167 AN: 152308 Hom.: 15 Cov.: 32 AF XY: 0.00741 AC XY: 552 AN XY: 74466

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00409 Hom.: 4

Bravo AF: 0.00872

ExAC AF: 0.00187 AC: 43

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ala2271Thr in exon 40 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 6.8% (12/176) of Yoruba (Nigerian) c hromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi. nlm.nih.gov/projects/SNP; dbSNP rs116503251). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	9.5
Dann	Benign	0.33
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.070	N;.
REVEL	Benign	0.015
Sift	Benign	0.55	T;.
Sift4G	Benign	0.17	T;T
Vest4		0.094
MVP		0.055
ClinPred		0.0019	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs116503251; hg19: chr11-17653311; COSMIC: COSV99063481;