12-80210987-A-G

Variant names:

• chr12-80210987-A-G
• rs80086846
• NM_001378609.3:c.119+101A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.119+101A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 736,440 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 32)
  • Exomes 𝑓: 0.022 (197 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.500
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-80210987-A-G is Benign according to our data. Variant chr12-80210987-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1211128.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 = 0.0138 (2101/152220) while in subpopulation NFE AF = 0.0235 (1601/67988). AF 95% confidence interval is 0.0226. There are 21 homozygotes in GnomAd4. There are 983 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.119+101A>G		intron_variant	Intron 3 of 58	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.119+101A>G		intron_variant	Intron 3 of 58	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.119+101A>G		intron_variant	Intron 8 of 62			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.779+101A>G		intron_variant	Intron 6 of 22

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2101 AN: 152102 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.00958

GnomAD4 exome AF: 0.0222 AC: 12969 AN: 584220 Hom.: 197 AF XY: 0.0216 AC XY: 6317 AN XY: 291992

African (AFR) AF: 0.00421 AC: 54 AN: 12822

American (AMR) AF: 0.00563 AC: 53 AN: 9406

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 175 AN: 13400

East Asian (EAS) AF: 0.000123 AC: 3 AN: 24452

South Asian (SAS) AF: 0.00890 AC: 181 AN: 20340

European-Finnish (FIN) AF: 0.00874 AC: 207 AN: 23674

Middle Eastern (MID) AF: 0.00592 AC: 22 AN: 3714

European-Non Finnish (NFE) AF: 0.0260 AC: 11658 AN: 448678

Other (OTH) AF: 0.0222 AC: 616 AN: 27734

GnomAD4 genome AF: 0.0138 AC: 2101 AN: 152220 Hom.: 21 Cov.: 32 AF XY: 0.0132 AC XY: 983 AN XY: 74422

African (AFR) AF: 0.00426 AC: 177 AN: 41560

American (AMR) AF: 0.00543 AC: 83 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4824

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1601 AN: 67988

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.0201 Hom.: 58

Bravo AF: 0.0126

Asia WGS AF: 0.00290 AC: 10 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.9
DANN	Benign	0.85
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism

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: rs80086846; hg19: chr12-80604767;