rs754987281

Variant names:

• chr12-80222079-GT-G
• rs754987281
• NM_001378609.3:c.335-9delT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001378609.3(OTOGL):​c.335-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,592,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.64
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-80222079-GT-G is Benign according to our data. Variant chr12-80222079-GT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517312.

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.335-9delT		intron	N/A	NP_001365538.2
	OTOGL	NM_001378610.3		c.335-9delT		intron	N/A	NP_001365539.2
	OTOGL	NM_173591.7		c.335-9delT		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.335-11delT		intron	N/A	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.335-11delT		intron	N/A	ENSP00000496036.1
	OTOGL	ENST00000643417.1		n.995-11delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 44 AN: 230474 AF XY: 0.000230

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000689

GnomAD4 exome AF: 0.000185 AC: 266 AN: 1440562 Hom.: 0 Cov.: 30 AF XY: 0.000198 AC XY: 142 AN XY: 717096

African (AFR) AF: 0.0000302 AC: 1 AN: 33152

American (AMR) AF: 0.000205 AC: 9 AN: 43954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85420

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39018

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5722

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1107854

Other (OTH) AF: 0.000383 AC: 23 AN: 60012

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74438

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.000262 AC: 4 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000287

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs754987281; hg19: chr12-80615859;