chr12-80211020-A-C

Variant names:

• chr12-80211020-A-C
• rs17006505
• NM_001378609.3:c.119+134A>C

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.119+134A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00591 in 512,904 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (14 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.286
• 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=-0.86).
• BP6: Variant 12-80211020-A-C is Benign according to our data. Variant chr12-80211020-A-C is described in ClinVar as [Benign]. Clinvar id is 1267402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.119+134A>C		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+134A>C		intron_variant	Intron 3 of 58	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.119+134A>C		intron_variant	Intron 8 of 62			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.779+134A>C		intron_variant	Intron 6 of 22

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2380 AN: 152126 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00862

GnomAD4 exome AF: 0.00181 AC: 651 AN: 360660 Hom.: 14 AF XY: 0.00163 AC XY: 298 AN XY: 182694

African (AFR) AF: 0.0517 AC: 456 AN: 8814

American (AMR) AF: 0.00441 AC: 35 AN: 7930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10312

East Asian (EAS) AF: 0.00 AC: 0 AN: 23310

South Asian (SAS) AF: 0.000103 AC: 1 AN: 9666

European-Finnish (FIN) AF: 0.000320 AC: 7 AN: 21886

Middle Eastern (MID) AF: 0.00133 AC: 4 AN: 3012

European-Non Finnish (NFE) AF: 0.000156 AC: 40 AN: 255592

Other (OTH) AF: 0.00536 AC: 108 AN: 20138

GnomAD4 genome AF: 0.0156 AC: 2380 AN: 152244 Hom.: 73 Cov.: 32 AF XY: 0.0156 AC XY: 1165 AN XY: 74454

African (AFR) AF: 0.0543 AC: 2255 AN: 41542

American (AMR) AF: 0.00628 AC: 96 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0125 Hom.: 4

Bravo AF: 0.0179

Asia WGS AF: 0.00406 AC: 14 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 10, 2018

GeneDx

Significance: 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	-0.86
CADD	Benign	0.35
DANN	Benign	0.62
PhyloP100		-0.29
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: rs17006505; hg19: chr12-80604800;