chr11-17559660-A-G

Variant names:

• chr11-17559660-A-G
• rs115772736
• NM_001292063.2:c.1340A>G

Variant summary

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

The NM_001277269.2(OTOG):​c.1376A>G​(p.Asn459Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000444 in 1,550,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: OTOG NM_001277269.2 missense, splice_region
• Scores: Splicing: ADA: 0.1068
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.85
• 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), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010245383).
• BP6: Variant 11-17559660-A-G is Benign according to our data. Variant chr11-17559660-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504781.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 = 0.00221 (336/152152) while in subpopulation AFR AF = 0.0077 (320/41542). AF 95% confidence interval is 0.00701. There are 2 homozygotes in GnomAd4. There are 157 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_001277269.2. 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.1340A>G	p.Asn447Ser	missense splice_region	Exon 12 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.1376A>G	p.Asn459Ser	missense splice_region	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.1340A>G	p.Asn447Ser	missense splice_region	Exon 12 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.1376A>G	p.Asn459Ser	missense splice_region	Exon 11 of 55	ENSP00000382323.2
	OTOG	ENST00000498332.5	TSL:5	n.1246A>G		splice_region non_coding_transcript_exon	Exon 11 of 16

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152036 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.00143

GnomAD2 exomes AF: 0.000474 AC: 71 AN: 149798 AF XY: 0.000348

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000461

GnomAD4 exome AF: 0.000252 AC: 353 AN: 1398038 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 140 AN XY: 689526

African (AFR) AF: 0.00807 AC: 255 AN: 31584

American (AMR) AF: 0.000476 AC: 17 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35712

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48148

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5698

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1078782

Other (OTH) AF: 0.00100 AC: 58 AN: 58028

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152152 Hom.: 2 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74388

African (AFR) AF: 0.00770 AC: 320 AN: 41542

American (AMR) AF: 0.000654 AC: 10 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00214 Hom.: 0

Bravo AF: 0.00241

ExAC AF: 0.000494 AC: 13

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.38	N
PhyloP100		4.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.096
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Vest4		0.11
MVP		0.19
ClinPred		0.022	T
GERP RS		4.4
Varity_R		0.053
gMVP		0.35
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115772736; hg19: chr11-17581207;