rs199674686

Variant names:

• chr12-80251813-T-C
• rs199674686
• NM_001378609.3:c.1159+14T>C

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.1159+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,551,972 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (39 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.204
• 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=-0.83).
• BP6: Variant 12-80251813-T-C is Benign according to our data. Variant chr12-80251813-T-C is described in ClinVar as Benign. ClinVar VariationId is 226927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (233/152262) while in subpopulation SAS AF = 0.0147 (71/4822). AF 95% confidence interval is 0.012. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 39 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.1159+14T>C		intron	N/A	NP_001365538.2
	OTOGL	NM_001378610.3		c.1159+14T>C		intron	N/A	NP_001365539.2
	OTOGL	NM_173591.7		c.1159+14T>C		intron	N/A	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.1159+14T>C		intron	N/A	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.1159+14T>C		intron	N/A	ENSP00000496036.1
	OTOGL	ENST00000643417.1		n.1819+14T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00381 AC: 612 AN: 160764 AF XY: 0.00446

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00647

GnomAD4 exome AF: 0.00200 AC: 2799 AN: 1399710 Hom.: 39 Cov.: 29 AF XY: 0.00247 AC XY: 1710 AN XY: 691196

African (AFR) AF: 0.000344 AC: 11 AN: 31932

American (AMR) AF: 0.00161 AC: 58 AN: 36066

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 515 AN: 25144

East Asian (EAS) AF: 0.0000548 AC: 2 AN: 36520

South Asian (SAS) AF: 0.0137 AC: 1086 AN: 79338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49914

Middle Eastern (MID) AF: 0.0196 AC: 111 AN: 5676

European-Non Finnish (NFE) AF: 0.000761 AC: 820 AN: 1077060

Other (OTH) AF: 0.00338 AC: 196 AN: 58060

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74442

African (AFR) AF: 0.000120 AC: 5 AN: 41538

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00436 Hom.: 2

Bravo AF: 0.00129

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.57
PhyloP100		-0.20
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: rs199674686; hg19: chr12-80645593;