rs201371081

Variant names:

• chr11-17612617-C-G
• rs201371081
• NM_001292063.2:c.6293-3C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-17612617-C-G
• chr11-17612617-C-T
• chr11-17612617-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001292063.2(OTOG):​c.6293-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,397,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.6293-3C>G		splice_region intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.6329-3C>G		splice_region intron	N/A	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.6293-3C>G		splice_region intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.6329-3C>G		splice_region intron	N/A	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.3631-3C>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000202 AC: 3 AN: 148458 AF XY: 0.0000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1397328 Hom.: 0 Cov.: 31 AF XY: 0.0000145 AC XY: 10 AN XY: 689074

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.0000561 AC: 2 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48178

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5670

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078346

Other (OTH) AF: 0.0000345 AC: 2 AN: 57984

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.81		Position offset: 3

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

Other links and lift over

dbSNP: rs201371081; hg19: chr11-17634164;