rs10862089

Variant names:

• chr12-80305695-G-T
• rs10862089
• NM_001378609.3:c.3333G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.3333G>T​(p.Gln1111His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.08 in 1,521,884 control chromosomes in the GnomAD database, including 5,234 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (542 hom., cov: 33)
  • Exomes 𝑓: 0.080 (4692 hom.)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Scores: Splicing: ADA: 0.7123
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.06
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030183494).
• BP6: Variant 12-80305695-G-T is Benign according to our data. Variant chr12-80305695-G-T is described in ClinVar as Benign. ClinVar VariationId is 226940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 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.3333G>T	p.Gln1111His	missense splice_region	Exon 29 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.3333G>T	p.Gln1111His	missense splice_region	Exon 32 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.3333G>T	p.Gln1111His	missense splice_region	Exon 29 of 59	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.3333G>T	p.Gln1111His	missense splice_region	Exon 29 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.3198G>T	p.Gln1066His	missense splice_region	Exon 33 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes AF: 0.0800 AC: 12163 AN: 151952 Hom.: 539 Cov.: 33

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.0584

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.0453

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0789

GnomAD2 exomes AF: 0.0894 AC: 16728 AN: 187164 AF XY: 0.0900

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0658

Gnomad EAS exome AF: 0.0428

Gnomad FIN exome AF: 0.0597

Gnomad NFE exome AF: 0.0812

Gnomad OTH exome AF: 0.0820

GnomAD4 exome AF: 0.0800 AC: 109583 AN: 1369814 Hom.: 4692 Cov.: 30 AF XY: 0.0815 AC XY: 55461 AN XY: 680408

African (AFR) AF: 0.0739 AC: 2250 AN: 30434

American (AMR) AF: 0.142 AC: 4142 AN: 29242

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 1440 AN: 23088

East Asian (EAS) AF: 0.0359 AC: 1350 AN: 37652

South Asian (SAS) AF: 0.132 AC: 9329 AN: 70906

European-Finnish (FIN) AF: 0.0630 AC: 2321 AN: 36824

Middle Eastern (MID) AF: 0.0801 AC: 435 AN: 5428

European-Non Finnish (NFE) AF: 0.0778 AC: 83952 AN: 1079748

Other (OTH) AF: 0.0772 AC: 4364 AN: 56492

GnomAD4 genome AF: 0.0800 AC: 12166 AN: 152070 Hom.: 542 Cov.: 33 AF XY: 0.0802 AC XY: 5961 AN XY: 74344

African (AFR) AF: 0.0725 AC: 3006 AN: 41484

American (AMR) AF: 0.113 AC: 1723 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3472

East Asian (EAS) AF: 0.0454 AC: 235 AN: 5172

South Asian (SAS) AF: 0.136 AC: 658 AN: 4826

European-Finnish (FIN) AF: 0.0589 AC: 623 AN: 10570

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5444 AN: 67952

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0799 Hom.: 2017

Bravo AF: 0.0819

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0776 AC: 299

ESP6500AA AF: 0.0722 AC: 261

ESP6500EA AF: 0.0767 AC: 624

ExAC AF: 0.0884 AC: 10504

Asia WGS AF: 0.0950 AC: 331 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Vest4		0.37
MutPred		0.60		Gain of catalytic residue at Q1102 (P = 0.0068)
MPC		0.10
ClinPred		0.014	T
GERP RS		3.1
gMVP		0.67
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10862089; hg19: chr12-80699475; COSMIC: COSV107534385;