rs117380920

Variant names:

• chr11-17609906-C-T
• rs117380920
• NM_001292063.2:c.4606C>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.4606C>T​(p.Leu1536Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,521,602 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (87 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.469
• Publications: 7 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=0.0030214787).
• BP6: Variant 11-17609906-C-T is Benign according to our data. Variant chr11-17609906-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00798 (1213/152080) while in subpopulation AMR AF = 0.0126 (192/15288). AF 95% confidence interval is 0.0111. There are 9 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4606C>T	p.Leu1536Phe	missense	Exon 36 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.4642C>T	p.Leu1548Phe	missense	Exon 35 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.4606C>T	p.Leu1536Phe	missense	Exon 36 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.4642C>T	p.Leu1548Phe	missense	Exon 35 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.1944C>T		non_coding_transcript_exon	Exon 12 of 22

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1215 AN: 151962 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00201

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00823 AC: 1023 AN: 124278 AF XY: 0.00822

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00825

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00318

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0110 AC: 15009 AN: 1369522 Hom.: 87 Cov.: 31 AF XY: 0.0110 AC XY: 7365 AN XY: 671574

African (AFR) AF: 0.00218 AC: 68 AN: 31224

American (AMR) AF: 0.00913 AC: 310 AN: 33970

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 488 AN: 22864

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35514

South Asian (SAS) AF: 0.00263 AC: 194 AN: 73644

European-Finnish (FIN) AF: 0.00316 AC: 148 AN: 46788

Middle Eastern (MID) AF: 0.0130 AC: 72 AN: 5528

European-Non Finnish (NFE) AF: 0.0124 AC: 13179 AN: 1063200

Other (OTH) AF: 0.00967 AC: 549 AN: 56790

GnomAD4 genome AF: 0.00798 AC: 1213 AN: 152080 Hom.: 9 Cov.: 32 AF XY: 0.00772 AC XY: 574 AN XY: 74336

African (AFR) AF: 0.00198 AC: 82 AN: 41488

American (AMR) AF: 0.0126 AC: 192 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4810

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 781 AN: 67958

Other (OTH) AF: 0.0133 AC: 28 AN: 2106

Alfa AF: 0.00823 Hom.: 4

Bravo AF: 0.00907

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0112 AC: 43

ExAC AF: 0.00389 AC: 112

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Meniere disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.47
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.040
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.056	T
Vest4		0.045
MVP		0.095
ClinPred		0.0042	T
GERP RS		2.4
Varity_R		0.068
gMVP		0.28
Mutation Taster		=96/4	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: rs117380920; hg19: chr11-17631453; COSMIC: COSV99063455;