rs542442173

Positions:

• chr11-17640784-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001292063.2(OTOG):​c.7975G>A​(p.Val2659Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,550,278 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.24

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008723229).
• BP6: Variant 11-17640784-G-A is Benign according to our data. Variant chr11-17640784-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227802.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7975G>A	p.Val2659Met	missense_variant	50/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8011G>A	p.Val2671Met	missense_variant	49/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7975G>A	p.Val2659Met	missense_variant	50/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8011G>A	p.Val2671Met	missense_variant	49/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000129 AC: 19 AN: 147820 Hom.: 0 AF XY: 0.000126 AC XY: 10 AN XY: 79516

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.0000815

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: 0.0000369

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000122 AC: 171 AN: 1397898 Hom.: 1 Cov.: 34 AF XY: 0.000112 AC XY: 77 AN XY: 689424

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000741

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74530

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000540

ExAC AF: 0.0000424 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2671 of the OTOG protein (p.Val2671Met). This variant is present in population databases (rs542442173, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 227802). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2016

p.Val267Met in exon 49 of OTOG: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, four mammals have a methionine (Met) at this position. It has been identifi ed in 1/5042 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org;dbSNP rs542442173). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.032
Sift	Benign	0.23	T;.
Sift4G	Benign	0.11	T;T
Vest4		0.087
MVP		0.081
ClinPred		0.0086	T
GERP RS		3.3
Varity_R		0.039
gMVP		0.40

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: rs542442173; hg19: chr11-17662331;