11-17555877-G-T

Variant names:

• chr11-17555877-G-T
• rs61736015
• NM_001292063.2:c.639G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.639G>T​(p.Glu213Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,551,036 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E213E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0740
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• 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=0.0077190697).
• BP6: Variant 11-17555877-G-T is Benign according to our data. Variant chr11-17555877-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227791.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 = 0.0032 (487/152318) while in subpopulation AFR AF = 0.0113 (470/41568). AF 95% confidence interval is 0.0105. There are 2 homozygotes in GnomAd4. There are 236 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.639G>T	p.Glu213Asp	missense	Exon 7 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.675G>T	p.Glu225Asp	missense	Exon 6 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.639G>T	p.Glu213Asp	missense	Exon 7 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.675G>T	p.Glu225Asp	missense	Exon 6 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000485669.1	TSL:4	n.178G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000556 AC: 84 AN: 151052 AF XY: 0.000432

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000263 AC: 368 AN: 1398718 Hom.: 2 Cov.: 30 AF XY: 0.000244 AC XY: 168 AN XY: 689862

African (AFR) AF: 0.0102 AC: 321 AN: 31596

American (AMR) AF: 0.000364 AC: 13 AN: 35708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48406

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079028

Other (OTH) AF: 0.000516 AC: 30 AN: 58130

GnomAD4 genome AF: 0.00320 AC: 487 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.00317 AC XY: 236 AN XY: 74472

African (AFR) AF: 0.0113 AC: 470 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00369

ExAC AF: 0.000454 AC: 10

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.074
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.081
Sift	Uncertain	0.027	D
Sift4G	Benign	0.15	T
Vest4		0.22
MutPred		0.42		Gain of ubiquitination at K224 (P = 0.1162)
MVP		0.14
ClinPred		0.041	T
GERP RS		-3.0
Varity_R		0.097
gMVP		0.36
Mutation Taster		=89/11	polymorphism

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: rs61736015; hg19: chr11-17577424;