rs547173007

Positions:

• chr11-17572108-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001292063.2(OTOG):​c.1984C>T​(p.Pro662Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000437 in 1,550,430 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (4 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.85

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011637777).
• BP6: Variant 11-17572108-C-T is Benign according to our data. Variant chr11-17572108-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.1984C>T	p.Pro662Ser	missense_variant	18/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2020C>T	p.Pro674Ser	missense_variant	17/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.1984C>T	p.Pro662Ser	missense_variant	18/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.2020C>T	p.Pro674Ser	missense_variant	17/55	5		ENSP00000382323	A2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000798 AC: 118 AN: 147842 Hom.: 1 AF XY: 0.000991 AC XY: 79 AN XY: 79712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.00266

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.000567

Gnomad OTH exome AF: 0.000936

GnomAD4 exome AF: 0.000443 AC: 619 AN: 1398266 Hom.: 4 Cov.: 30 AF XY: 0.000532 AC XY: 367 AN XY: 689672

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.000104

Gnomad4 NFE exome AF: 0.000316

Gnomad4 OTH exome AF: 0.000379

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.000336

ExAC AF: 0.00140 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Pro674Ser var iant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 0.26% (58/22594) of South Asian chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org/; dbSNP rs547173007). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong s upport for or against an impact to the protein. In summary, while the clinical s ignificance of the p.Pro674Ser variant is uncertain, its frequency suggests that it is more likely to be benign. -

OTOG-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.1	D;.
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0060	D;D
Vest4		0.50
MVP		0.22
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.42
gMVP		0.81

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: rs547173007; hg19: chr11-17593655;