NM_001378609.3:c.4446T>C

Variant names:

• chr12-80335986-T-C
• rs376273459
• NM_001378609.3:c.4446T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001378609.3(OTOGL):​c.4446T>C​(p.Tyr1482Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,584,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-80335986-T-C is Benign according to our data. Variant chr12-80335986-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 504795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.

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.4446T>C	p.Tyr1482Tyr	synonymous	Exon 39 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.4446T>C	p.Tyr1482Tyr	synonymous	Exon 42 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.4446T>C	p.Tyr1482Tyr	synonymous	Exon 39 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.4446T>C	p.Tyr1482Tyr	synonymous	Exon 39 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.4311T>C	p.Tyr1437Tyr	synonymous	Exon 43 of 63	ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000629 AC: 14 AN: 222422 AF XY: 0.0000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 219 AN: 1432576 Hom.: 0 Cov.: 30 AF XY: 0.000133 AC XY: 95 AN XY: 712300

African (AFR) AF: 0.00 AC: 0 AN: 32854

American (AMR) AF: 0.0000238 AC: 1 AN: 42066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.00 AC: 0 AN: 83000

European-Finnish (FIN) AF: 0.0000257 AC: 1 AN: 38890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000189 AC: 209 AN: 1105484

Other (OTH) AF: 0.000134 AC: 8 AN: 59712

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.2
DANN	Benign	0.44
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376273459; hg19: chr12-80729766;