rs1003490

Positions:

• chr11-17610759-C-G
• chr11-17610759-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.5459C>G​(p.Ala1820Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,549,914 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1820V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (19 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.45

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036871433).
• BP6: Variant 11-17610759-C-G is Benign according to our data. Variant chr11-17610759-C-G is described in ClinVar as [Benign]. Clinvar id is 226897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00935 (1424/152284) while in subpopulation AFR AF= 0.0326 (1357/41570). AF 95% confidence interval is 0.0312. There are 20 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.5459C>G	p.Ala1820Gly	missense_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.5495C>G	p.Ala1832Gly	missense_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.5459C>G	p.Ala1820Gly	missense_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.5495C>G	p.Ala1832Gly	missense_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.2797C>G		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00935 AC: 1422 AN: 152166 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00192 AC: 285 AN: 148604 Hom.: 4 AF XY: 0.00141 AC XY: 113 AN XY: 79980

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00155

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: 0.0000543

Gnomad OTH exome AF: 0.000695

GnomAD4 exome AF: 0.000972 AC: 1359 AN: 1397630 Hom.: 19 Cov.: 69 AF XY: 0.000812 AC XY: 560 AN XY: 689360

Gnomad4 AFR exome AF: 0.0348

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000556

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00935 AC: 1424 AN: 152284 Hom.: 20 Cov.: 33 AF XY: 0.00900 AC XY: 670 AN XY: 74458

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.0000670 Hom.: 2108

ExAC AF: 0.00202 AC: 52

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 20, 2015	p.Ala1832Gly in exon 35 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 3.6% (34/940) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs1003490). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.71	N;.
REVEL	Benign	0.069
Sift	Benign	0.043	D;.
Sift4G	Benign	0.16	T;T
Vest4		0.32
MVP		0.25
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.39

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: rs1003490; hg19: chr11-17632306; COSMIC: COSV61135420;