rs548278514

chr11-17634873-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.7510G>A(p.Ala2504Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,475,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.32

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=0.008938849).
• BP6: Variant 11-17634873-G-A is Benign according to our data. Variant chr11-17634873-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227795.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7510G>A	p.Ala2504Thr	missense_variant	45/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7546G>A	p.Ala2516Thr	missense_variant	44/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7510G>A	p.Ala2504Thr	missense_variant	45/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7546G>A	p.Ala2516Thr	missense_variant	44/55	5		A2
OTOG	ENST00000342528.2	n.4606-737G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 173 AN: 147246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000404

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00293

GnomAD3 exomes AF: 0.000232 AC: 34 AN: 146336 Hom.: 0 AF XY: 0.000152 AC XY: 12 AN XY: 78958

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.000489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000888

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000236

GnomAD4 exome AF: 0.000126 AC: 168 AN: 1328540 Hom.: 0 Cov.: 33 AF XY: 0.0000993 AC XY: 65 AN XY: 654402

Gnomad4 AFR exome AF: 0.00336

Gnomad4 AMR exome AF: 0.000538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000348

Gnomad4 OTH exome AF: 0.000244

GnomAD4 genome AF: 0.00117 AC: 173 AN: 147376 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 84 AN XY: 71868

Gnomad4 AFR AF: 0.00394

Gnomad4 AMR AF: 0.000403

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00290

Alfa AF: 0.000820 Hom.: 0

Bravo AF: 0.00127

ExAC AF: 0.000100 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 23, 2016

p.Ala2516Thr in exon 44 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals, sug gesting that variants at this position are tolerated. Of note, 5 mammals (Bactri an camel, elephant shrew, oposum, Tasmanian devil, and wallaby) have a threonine (Thr) this position despite high nearby amino acid conservation. In addition, c omputational prediction tools do not suggest a high likelihood of impact to the protein. The variant has been reported in 2/802 African chromosomes by the Exome Aggregate Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs548278514) . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.023
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.037
Sift	Benign	0.32	T;T
Sift4G	Benign	0.49	T;T
Vest4		0.068
MVP		0.21
ClinPred		0.033	T
GERP RS		4.2
Varity_R		0.030
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs548278514; hg19: chr11-17656420; COSMIC: COSV100696280;