rs10778725

Variant names:

• chr12-80318640-G-A
• rs10778725
• NM_001378609.3:c.3729G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-80318640-G-A
• chr12-80318640-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.3729G>A​(p.Pro1243Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,468,996 control chromosomes in the GnomAD database, including 697,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70633 hom., cov: 31)
  • Exomes 𝑓: 0.98 (627033 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.525
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-80318640-G-A is Benign according to our data. Variant chr12-80318640-G-A is described in ClinVar as Benign. ClinVar VariationId is 226944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.525 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 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.3729G>A	p.Pro1243Pro	synonymous	Exon 33 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.3729G>A	p.Pro1243Pro	synonymous	Exon 36 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.3729G>A	p.Pro1243Pro	synonymous	Exon 33 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.3729G>A	p.Pro1243Pro	synonymous	Exon 33 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.3594G>A	p.Pro1198Pro	synonymous	Exon 37 of 63	ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146431 AN: 152102 Hom.: 70575 Cov.: 31

Gnomad AFR AF: 0.955

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.974

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.972

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.972

GnomAD2 exomes AF: 0.949 AC: 99078 AN: 104450 AF XY: 0.952

Gnomad AFR exome AF: 0.945

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.973

Gnomad EAS exome AF: 0.934

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.960

GnomAD4 exome AF: 0.976 AC: 1284595 AN: 1316776 Hom.: 627033 Cov.: 43 AF XY: 0.975 AC XY: 631963 AN XY: 648196

African (AFR) AF: 0.954 AC: 25878 AN: 27122

American (AMR) AF: 0.844 AC: 20187 AN: 23916

Ashkenazi Jewish (ASJ) AF: 0.972 AC: 22107 AN: 22738

East Asian (EAS) AF: 0.954 AC: 30240 AN: 31704

South Asian (SAS) AF: 0.944 AC: 60553 AN: 64130

European-Finnish (FIN) AF: 0.972 AC: 45660 AN: 46956

Middle Eastern (MID) AF: 0.983 AC: 5274 AN: 5364

European-Non Finnish (NFE) AF: 0.982 AC: 1022209 AN: 1040878

Other (OTH) AF: 0.973 AC: 52487 AN: 53968

GnomAD4 genome AF: 0.963 AC: 146548 AN: 152220 Hom.: 70633 Cov.: 31 AF XY: 0.961 AC XY: 71483 AN XY: 74416

African (AFR) AF: 0.955 AC: 39661 AN: 41528

American (AMR) AF: 0.898 AC: 13711 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.974 AC: 3381 AN: 3472

East Asian (EAS) AF: 0.949 AC: 4905 AN: 5170

South Asian (SAS) AF: 0.938 AC: 4526 AN: 4826

European-Finnish (FIN) AF: 0.972 AC: 10313 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66805 AN: 68014

Other (OTH) AF: 0.973 AC: 2058 AN: 2116

Alfa AF: 0.970 Hom.: 46204

Bravo AF: 0.956

Asia WGS AF: 0.943 AC: 3274 AN: 3470

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	-0.70
CADD	Benign	5.5
DANN	Benign	0.51
PhyloP100		0.53
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: rs10778725; hg19: chr12-80712420; COSMIC: COSV108261577;