rs61910753

Variant names:

• chr11-17557146-G-A
• rs61910753
• NM_001292063.2:c.688G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.688G>A​(p.Ala230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,550,382 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. A230V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (183 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (138 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.433
• Publications: 2 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026563108).
• BP6: Variant 11-17557146-G-A is Benign according to our data. Variant chr11-17557146-G-A is described in ClinVar as Benign. ClinVar VariationId is 226906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.688G>A	p.Ala230Thr	missense	Exon 8 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.724G>A	p.Ala242Thr	missense	Exon 7 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.688G>A	p.Ala230Thr	missense	Exon 8 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.724G>A	p.Ala242Thr	missense	Exon 7 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000485669.1	TSL:4	n.227G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4063 AN: 152088 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

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: 0.000162

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00533 AC: 795 AN: 149192 AF XY: 0.00405

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000200

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00269 AC: 3758 AN: 1398178 Hom.: 138 Cov.: 32 AF XY: 0.00227 AC XY: 1565 AN XY: 689612

African (AFR) AF: 0.0965 AC: 3048 AN: 31598

American (AMR) AF: 0.00473 AC: 169 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000177 AC: 14 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48064

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5690

European-Non Finnish (NFE) AF: 0.000127 AC: 137 AN: 1078974

Other (OTH) AF: 0.00641 AC: 372 AN: 57992

GnomAD4 genome AF: 0.0267 AC: 4065 AN: 152204 Hom.: 183 Cov.: 32 AF XY: 0.0260 AC XY: 1936 AN XY: 74400

African (AFR) AF: 0.0940 AC: 3901 AN: 41498

American (AMR) AF: 0.00739 AC: 113 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0226 Hom.: 101

Bravo AF: 0.0303

ExAC AF: 0.00569 AC: 131

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.43
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.045
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.026	D
Vest4		0.19
MVP		0.085
ClinPred		0.0087	T
GERP RS		-7.3
Varity_R		0.061
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61910753; hg19: chr11-17578693; COSMIC: COSV108927512; COSMIC: COSV108927512;