rs77835094

Positions:

• chr12-80271679-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001378609.3(OTOGL):​c.2550C>T​(p.Phe850=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,612,896 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (14 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.317

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 12-80271679-C-T is Benign according to our data. Variant chr12-80271679-C-T is described in ClinVar as [Benign]. Clinvar id is 226933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80271679-C-T is described in Lovd as [Benign]. Variant chr12-80271679-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.317 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00122 (186/152118) while in subpopulation EAS AF= 0.0175 (90/5152). AF 95% confidence interval is 0.0146. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.2550C>T	p.Phe850=	synonymous_variant	24/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.2550C>T	p.Phe850=	synonymous_variant	24/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.2550C>T	p.Phe850=	synonymous_variant	29/63

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152000 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00257 AC: 631 AN: 245792 Hom.: 6 AF XY: 0.00234 AC XY: 313 AN XY: 133546

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0198

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00586

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.000974 AC: 1423 AN: 1460778 Hom.: 14 Cov.: 32 AF XY: 0.000928 AC XY: 674 AN XY: 726676

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00523

Gnomad4 NFE exome AF: 0.000311

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152118 Hom.: 1 Cov.: 32 AF XY: 0.00139 AC XY: 103 AN XY: 74348

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000713 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Phe841Phe in exon 23 of OTOGL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 1.9% (11/572) of Ea st Asian chromosomes from a broad population by the 1000 Genomes Project (http:/ /www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs77835094). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	5.5
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77835094; hg19: chr12-80665459;