rs200889330

Variant names:

• chr12-80329046-T-C
• rs200889330
• NM_001378609.3:c.4280-5T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001378609.3(OTOGL):​c.4280-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,588,454 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (2 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004341
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.32
• Publications: 0 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-80329046-T-C is Benign according to our data. Variant chr12-80329046-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. 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
	OTOGL	NM_001378609.3	MANE Select	c.4280-5T>C		splice_region intron	N/A	NP_001365538.2
	OTOGL	NM_001378610.3		c.4280-5T>C		splice_region intron	N/A	NP_001365539.2
	OTOGL	NM_173591.7		c.4280-5T>C		splice_region intron	N/A	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.4280-5T>C		splice_region intron	N/A	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.4145-5T>C		splice_region intron	N/A	ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000778 AC: 169 AN: 217106 AF XY: 0.000808

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00262

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000898 AC: 1289 AN: 1436210 Hom.: 2 Cov.: 30 AF XY: 0.000840 AC XY: 599 AN XY: 713220

African (AFR) AF: 0.000124 AC: 4 AN: 32296

American (AMR) AF: 0.0000258 AC: 1 AN: 38814

Ashkenazi Jewish (ASJ) AF: 0.0000401 AC: 1 AN: 24924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80396

European-Finnish (FIN) AF: 0.00286 AC: 151 AN: 52814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.000987 AC: 1088 AN: 1102606

Other (OTH) AF: 0.000725 AC: 43 AN: 59316

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74388

African (AFR) AF: 0.000217 AC: 9 AN: 41462

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000521

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		3.3
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.030		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: rs200889330; hg19: chr12-80722826;