12-80336781-CTTT-CTT

Variant names:

• chr12-80336781-CT-C
• rs11300714
• NM_001378609.3:c.4744-5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.4744-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,133,276 control chromosomes in the GnomAD database, including 22,107 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3084 hom., cov: 26)
  • Exomes 𝑓: 0.26 (19023 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.465
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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 -16 ACMG points.

• BP6: Variant 12-80336781-CT-C is Benign according to our data. Variant chr12-80336781-CT-C is described in ClinVar as Benign. ClinVar VariationId is 226949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.4744-5delT		splice_region intron	N/A	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.4744-5delT		splice_region intron	N/A	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.4744-5delT		splice_region intron	N/A	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.4744-15delT		intron	N/A	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4609-15delT		intron	N/A	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.43-15delT		intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.202 AC: 29848 AN: 147718 Hom.: 3084 Cov.: 26

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.361 AC: 26828 AN: 74216 AF XY: 0.366

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.265 AC: 260919 AN: 985480 Hom.: 19023 Cov.: 0 AF XY: 0.267 AC XY: 129569 AN XY: 486034

African (AFR) AF: 0.280 AC: 6196 AN: 22110

American (AMR) AF: 0.282 AC: 7234 AN: 25610

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 4660 AN: 17146

East Asian (EAS) AF: 0.0900 AC: 1820 AN: 20212

South Asian (SAS) AF: 0.295 AC: 16264 AN: 55058

European-Finnish (FIN) AF: 0.191 AC: 5913 AN: 30942

Middle Eastern (MID) AF: 0.284 AC: 1055 AN: 3710

European-Non Finnish (NFE) AF: 0.269 AC: 207032 AN: 770016

Other (OTH) AF: 0.264 AC: 10745 AN: 40676

GnomAD4 genome AF: 0.202 AC: 29853 AN: 147796 Hom.: 3084 Cov.: 26 AF XY: 0.199 AC XY: 14304 AN XY: 71988

African (AFR) AF: 0.219 AC: 8869 AN: 40572

American (AMR) AF: 0.229 AC: 3394 AN: 14848

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 643 AN: 3398

East Asian (EAS) AF: 0.0512 AC: 258 AN: 5036

South Asian (SAS) AF: 0.224 AC: 1051 AN: 4686

European-Finnish (FIN) AF: 0.120 AC: 1142 AN: 9514

Middle Eastern (MID) AF: 0.250 AC: 70 AN: 280

European-Non Finnish (NFE) AF: 0.207 AC: 13757 AN: 66544

Other (OTH) AF: 0.203 AC: 410 AN: 2018

Alfa AF: 0.0871 Hom.: 104

Bravo AF: 0.204

ClinVar

ClinVar submissions

Significance: 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
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs11300714; hg19: chr12-80730561;