rs532385451

chr11-17634181-T-Achr11-17634181-T-C

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.7380T>A(p.Asp2460Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,550,258 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 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.800

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=0.0055246353).
• BP6: Variant 11-17634181-T-A is Benign according to our data. Variant chr11-17634181-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 229103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7380T>A	p.Asp2460Glu	missense_variant	44/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7416T>A	p.Asp2472Glu	missense_variant	43/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7380T>A	p.Asp2460Glu	missense_variant	44/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7416T>A	p.Asp2472Glu	missense_variant	43/55	5		A2
OTOG	ENST00000342528.2	n.4605+307T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.000265

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000443 AC: 65 AN: 146832 Hom.: 0 AF XY: 0.000316 AC XY: 25 AN XY: 79204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00216

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: 0.000203

Gnomad OTH exome AF: 0.000234

GnomAD4 exome AF: 0.000171 AC: 239 AN: 1398076 Hom.: 0 Cov.: 32 AF XY: 0.000155 AC XY: 107 AN XY: 689568

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74406

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000325

ExAC AF: 0.0000963 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2018

The p.Asp2472Glu variant in OTOG is classified as likely benign because it has b een identified in 0.2% (54/24684) of Latino chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org, dbSNP rs532385451) and the aspartic acid residue (Asp) at position 2472 is not conserved in mammals and ev olutionary distant species, raising the possibility that a change at this positi on may be tolerated. Computational prediction tools and conservation analysis su ggest that the p.Asp2472Glu variant may not impact the protein. In addition, thi s variant has previously been detected by our laboratory in an individual with h earing loss who was compound heterozygous for one likely pathogenic and one path ogenic GJB2 variants. ACMG/AMP Criteria applied: BS1_Supporting, BP4, PM5. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.9
Dann	Benign	0.74
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.57	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.012
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.046
MutPred		0.42		Gain of glycosylation at P2476 (P = 0.117);.;
MVP		0.030
ClinPred		0.037	T
GERP RS		-0.85
Varity_R		0.021
gMVP		0.36

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: rs532385451; hg19: chr11-17655728;