12-80341991-T-C

Variant names:

• chr12-80341991-T-C
• rs10778727
• NM_001378609.3:c.5094T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.5094T>C​(p.Asn1698Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,605,588 control chromosomes in the GnomAD database, including 306,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22649 hom., cov: 32)
  • Exomes 𝑓: 0.62 (283500 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.263
• Publications: 20 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.032).
• BP6: Variant 12-80341991-T-C is Benign according to our data. Variant chr12-80341991-T-C is described in ClinVar as Benign. ClinVar VariationId is 226952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.5094T>C	p.Asn1698Asn	synonymous	Exon 44 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.5094T>C	p.Asn1698Asn	synonymous	Exon 47 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.5094T>C	p.Asn1698Asn	synonymous	Exon 44 of 59	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5094T>C	p.Asn1698Asn	synonymous	Exon 44 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.4959T>C	p.Asn1653Asn	synonymous	Exon 48 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.393T>C	p.Asn131Asn	synonymous	Exon 5 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78823 AN: 151906 Hom.: 22649 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.584 AC: 139845 AN: 239328 AF XY: 0.596

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.620 AC: 900538 AN: 1453564 Hom.: 283500 Cov.: 41 AF XY: 0.621 AC XY: 448778 AN XY: 722732

African (AFR) AF: 0.240 AC: 8004 AN: 33394

American (AMR) AF: 0.415 AC: 18325 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 16129 AN: 26004

East Asian (EAS) AF: 0.726 AC: 28717 AN: 39534

South Asian (SAS) AF: 0.608 AC: 51692 AN: 85024

European-Finnish (FIN) AF: 0.687 AC: 36531 AN: 53204

Middle Eastern (MID) AF: 0.529 AC: 3028 AN: 5720

European-Non Finnish (NFE) AF: 0.634 AC: 701683 AN: 1106422

Other (OTH) AF: 0.606 AC: 36429 AN: 60142

GnomAD4 genome AF: 0.519 AC: 78837 AN: 152024 Hom.: 22649 Cov.: 32 AF XY: 0.523 AC XY: 38829 AN XY: 74308

African (AFR) AF: 0.256 AC: 10620 AN: 41494

American (AMR) AF: 0.479 AC: 7318 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3472

East Asian (EAS) AF: 0.718 AC: 3707 AN: 5162

South Asian (SAS) AF: 0.596 AC: 2873 AN: 4824

European-Finnish (FIN) AF: 0.683 AC: 7216 AN: 10560

Middle Eastern (MID) AF: 0.548 AC: 160 AN: 292

European-Non Finnish (NFE) AF: 0.635 AC: 43145 AN: 67936

Other (OTH) AF: 0.555 AC: 1170 AN: 2108

Alfa AF: 0.588 Hom.: 81076

Bravo AF: 0.488

Asia WGS AF: 0.631 AC: 2192 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.1
DANN	Benign	0.80
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10778727; hg19: chr12-80735771; COSMIC: COSV54014242; COSMIC: COSV54014242;