rs528799547

Variant names:

• chr11-17559606-G-A
• rs528799547
• NM_001292063.2:c.1286G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17559606-G-A
• chr11-17559606-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001292063.2(OTOG):​c.1286G>A​(p.Arg429Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,550,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R429W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.89
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008750081).
• BP6: Variant 11-17559606-G-A is Benign according to our data. Variant chr11-17559606-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.1286G>A	p.Arg429Gln	missense	Exon 12 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.1322G>A	p.Arg441Gln	missense	Exon 11 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.1286G>A	p.Arg429Gln	missense	Exon 12 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.1322G>A	p.Arg441Gln	missense	Exon 11 of 55	ENSP00000382323.2
	OTOG	ENST00000498332.5	TSL:5	n.1192G>A		non_coding_transcript_exon	Exon 11 of 16

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000825 AC: 124 AN: 150316 AF XY: 0.000755

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.0000813

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00289

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000719 AC: 1006 AN: 1398562 Hom.: 0 Cov.: 32 AF XY: 0.000697 AC XY: 481 AN XY: 689794

African (AFR) AF: 0.00117 AC: 37 AN: 31598

American (AMR) AF: 0.000224 AC: 8 AN: 35706

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

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79236

European-Finnish (FIN) AF: 0.00288 AC: 139 AN: 48290

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.000721 AC: 778 AN: 1079036

Other (OTH) AF: 0.000672 AC: 39 AN: 58076

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74460

African (AFR) AF: 0.00116 AC: 48 AN: 41556

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000937

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000525 AC: 19

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		2.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.063
Sift	Benign	0.22	T
Sift4G	Benign	0.40	T
Vest4		0.14
MVP		0.30
ClinPred		0.015	T
GERP RS		1.5
Varity_R		0.052
gMVP		0.29
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs528799547; hg19: chr11-17581153; COSMIC: COSV104704443; COSMIC: COSV104704443;