dbSNP rs79120261: OTOGL:c.5266-7T>C (chr12-80352288-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378609.3(OTOGL):c.5266-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,602,594 control chromosomes in the GnomAD database, including 809 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 56 hom., cov: 33)

Exomes 𝑓: 0.029 ( 753 hom. )

Consequence

OTOGL
NM_001378609.3 splice_region, intron

Scores

Splicing: ADA: 0.0004058

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.90

Publications

3 publications found

Variant links:

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

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 12-80352288-T-C is Benign according to our data. Variant chr12-80352288-T-C is described in ClinVar as Benign. ClinVar VariationId is 226954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3123/152284) while in subpopulation NFE AF = 0.0319 (2170/68008). AF 95% confidence interval is 0.0308. There are 56 homozygotes in GnomAd4. There are 1429 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTOGL	NM_001378609.3	MANE Select	c.5266-7T>C	splice_region intron	N/A	NP_001365538.2	Q3ZCN5
OTOGL	NM_001378610.3		c.5266-7T>C	splice_region intron	N/A	NP_001365539.2	Q3ZCN5
OTOGL	NM_173591.7		c.5266-7T>C	splice_region intron	N/A	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5266-7T>C	splice_region intron	N/A	ENSP00000447211.2	Q3ZCN5
OTOGL	ENST00000646859.1		c.5131-7T>C	splice_region intron	N/A	ENSP00000496036.1	A0A2R8YF04
OTOGL	ENST00000298820.7	TSL:5	c.565-7T>C	splice_region intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3122

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00649

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0319

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0196

AC:

4609

AN:

235408

AF XY:

0.0202

show subpopulations

Gnomad AFR exome

AF:

0.00601

Gnomad AMR exome

AF:

0.0155

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.000115

Gnomad FIN exome

AF:

0.00737

Gnomad NFE exome

AF:

0.0317

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0292

AC:

42280

AN:

1450310

Hom.:

753

Cov.:

AF XY:

0.0287

AC XY:

20672

AN XY:

721204

show subpopulations

African (AFR)

AF:

0.00638

AC:

210

AN:

32900

American (AMR)

AF:

0.0165

AC:

694

AN:

42118

Ashkenazi Jewish (ASJ)

AF:

0.0195

AC:

499

AN:

25550

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39518

South Asian (SAS)

AF:

0.00511

AC:

428

AN:

83814

European-Finnish (FIN)

AF:

0.00711

AC:

378

AN:

53142

Middle Eastern (MID)

AF:

0.0388

AC:

221

AN:

5696

European-Non Finnish (NFE)

AF:

0.0346

AC:

38306

AN:

1107682

Other (OTH)

AF:

0.0257

AC:

1542

AN:

59890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1760

3520

5279

7039

8799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1448

2896

4344

5792

7240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0205

AC:

3123

AN:

152284

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1429

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00654

AC:

272

AN:

41574

American (AMR)

AF:

0.0285

AC:

436

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00684

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0319

AC:

2170

AN:

68008

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0281

Hom.:

Bravo

AF:

0.0214

Asia WGS

AF:

0.00433

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

2.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00041

dbscSNV1_RF

Benign

0.010

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over