rs185895624

Positions:

• chr12-80341966-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.5069C>T​(p.Pro1690Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000357 in 1,604,484 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1690P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008742243).
• BP6: Variant 12-80341966-C-T is Benign according to our data. Variant chr12-80341966-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000316 (48/152038) while in subpopulation EAS AF= 0.00637 (33/5180). AF 95% confidence interval is 0.00466. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5069C>T	p.Pro1690Leu	missense_variant	44/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5069C>T	p.Pro1690Leu	missense_variant	44/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.4934C>T	p.Pro1645Leu	missense_variant	48/63
OTOGL	ENST00000298820.7	c.371C>T	p.Pro124Leu	missense_variant	5/18	5

Frequencies

GnomAD3 genomes AF: 0.000323 AC: 49 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00655

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000567 AC: 134 AN: 236456 Hom.: 2 AF XY: 0.000563 AC XY: 72 AN XY: 127906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.000617

Gnomad EAS exome AF: 0.00658

Gnomad SAS exome AF: 0.000139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000761

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000361 AC: 524 AN: 1452446 Hom.: 4 Cov.: 29 AF XY: 0.000366 AC XY: 264 AN XY: 721892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.000541

Gnomad4 EAS exome AF: 0.0108

Gnomad4 SAS exome AF: 0.000331

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74300

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000973 Hom.: 0

Bravo AF: 0.000389

ExAC AF: 0.000638 AC: 77

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Benign/Likely 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	Dec 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2015

p.Pro1681Leu in exon 43 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 1.2% (65/5238) of East Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs185895624). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
Vest4		0.73
MVP		0.48
MPC		0.19
ClinPred		0.12	T
GERP RS		5.1
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs185895624; hg19: chr12-80735746;