chr11-17608377-G-A

Position:

• chr11-17608377-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001292063.2(OTOG):​c.4238G>A​(p.Arg1413Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000466 in 1,546,540 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.12

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008218646).
• BP6: Variant 11-17608377-G-A is Benign according to our data. Variant chr11-17608377-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17608377-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.4238G>A	p.Arg1413Gln	missense_variant	34/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.4274G>A	p.Arg1425Gln	missense_variant	33/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.4238G>A	p.Arg1413Gln	missense_variant	34/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.4274G>A	p.Arg1425Gln	missense_variant	33/55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.1576G>A		non_coding_transcript_exon_variant	10/22	2

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000508 AC: 73 AN: 143590 Hom.: 0 AF XY: 0.000388 AC XY: 30 AN XY: 77408

Gnomad AFR exome AF: 0.00864

Gnomad AMR exome AF: 0.000558

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000465

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.000244

GnomAD4 exome AF: 0.000257 AC: 359 AN: 1394194 Hom.: 1 Cov.: 31 AF XY: 0.000215 AC XY: 148 AN XY: 687456

Gnomad4 AFR exome AF: 0.00881

Gnomad4 AMR exome AF: 0.000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000511

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000223

Gnomad4 OTH exome AF: 0.000570

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74504

Gnomad4 AFR AF: 0.00827

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00274

ExAC AF: 0.000546 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg1425Gln in exon 33 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 1.0% (5/492) of African chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs143848095). -

Autosomal recessive nonsyndromic hearing loss 18B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.036	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.64	N;.
REVEL	Benign	0.082
Sift	Benign	0.061	T;.
Sift4G	Uncertain	0.032	D;D
Vest4		0.21
MVP		0.33
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.078
gMVP		0.56

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: rs143848095; hg19: chr11-17629924; COSMIC: COSV100695720;