rs528799547

Positions:

• chr11-17559606-G-A
• chr11-17559606-G-T

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.1286G>A​(p.Arg429Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,550,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.89

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008750081).
• BP6: Variant 11-17559606-G-A is Benign according to our data. Variant chr11-17559606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.1286G>A	p.Arg429Gln	missense_variant	12/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.1322G>A	p.Arg441Gln	missense_variant	11/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.1286G>A	p.Arg429Gln	missense_variant	12/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.1322G>A	p.Arg441Gln	missense_variant	11/55	5		ENSP00000382323	A2
OTOG	ENST00000498332.5	n.1192G>A		non_coding_transcript_exon_variant	11/16	5

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000825 AC: 124 AN: 150316 Hom.: 1 AF XY: 0.000755 AC XY: 61 AN XY: 80752

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.0000813

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00289

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000719 AC: 1006 AN: 1398562 Hom.: 0 Cov.: 32 AF XY: 0.000697 AC XY: 481 AN XY: 689794

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00288

Gnomad4 NFE exome AF: 0.000721

Gnomad4 OTH exome AF: 0.000672

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74460

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000937

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000525 AC: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2015

p.Arg441Gln in exon 11 of OTOG: This variant is not expected to have clinical si gnificance because the arginine (Arg) at position 441 is not conserved through s pecies, with five mammals (Egyptian jerboa, brush-tailed rat, cat, tenrec, platy pus) having a glutamine (Gln) at this position. This variant has been identified in 0.43% (7/1632) of Finnish chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs528799547). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.48	N;.
REVEL	Benign	0.063
Sift	Benign	0.22	T;.
Sift4G	Benign	0.40	T;T
Vest4		0.14
MVP		0.30
ClinPred		0.015	T
GERP RS		1.5
Varity_R		0.052
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs528799547; hg19: chr11-17581153; COSMIC: COSV104704443; COSMIC: COSV104704443;