11-17547503-G-A

Position:

• chr11-17547503-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.94+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,326,700 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.185

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=0.002431661).
• BP6: Variant 11-17547503-G-A is Benign according to our data. Variant chr11-17547503-G-A is described in ClinVar as [Benign]. Clinvar id is 226863.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 = 0.0127 (1935/152194) while in subpopulation AFR AF= 0.0446 (1850/41514). AF 95% confidence interval is 0.0429. There are 49 homozygotes in gnomad4. There are 908 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.94+37G>A		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.131G>A	p.Arg44Gln	missense_variant	1/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.94+37G>A		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.131G>A	p.Arg44Gln	missense_variant	1/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1930 AN: 152076 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00240 AC: 23 AN: 9586 Hom.: 0 AF XY: 0.00245 AC XY: 13 AN XY: 5314

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00107 AC: 1258 AN: 1174506 Hom.: 26 Cov.: 31 AF XY: 0.000949 AC XY: 536 AN XY: 564914

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.00299

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000451

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000247

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.0127 AC: 1935 AN: 152194 Hom.: 49 Cov.: 32 AF XY: 0.0122 AC XY: 908 AN XY: 74402

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00207 Hom.: 1

Bravo AF: 0.0145

ExAC AF: 0.000690 AC: 12

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg44Gln in exon 1 of OTOG: This variant is not expected to have clinical signif icance because it has been identified in 4.5% (8/176) of Yoruba (Nigerian) chrom osomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm. nih.gov/projects/SNP; dbSNP rs111425080). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.86
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.0050
Sift	Benign	0.15	T
Sift4G	Uncertain	0.056	T
Vest4		0.055
MVP		0.048
ClinPred		0.0035	T
GERP RS		-1.8
Varity_R		0.020
gMVP		0.11

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: rs111425080; hg19: chr11-17569050;