NM_001378609.3:c.475C>T

Variant names:

• chr12-80222231-C-T
• rs191608225
• NM_001378609.3:c.475C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001378609.3(OTOGL):​c.475C>T​(p.Arg159Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000562 in 1,595,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (2 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.81

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12631842).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.475C>T	p.Arg159Trp	missense_variant	Exon 7 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.475C>T	p.Arg159Trp	missense_variant	Exon 7 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.475C>T	p.Arg159Trp	missense_variant	Exon 12 of 63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.1135C>T		non_coding_transcript_exon_variant	Exon 10 of 23

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000612 AC: 143 AN: 233556 Hom.: 0 AF XY: 0.000619 AC XY: 79 AN XY: 127646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000672

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000950

Gnomad NFE exome AF: 0.000984

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000574 AC: 828 AN: 1443690 Hom.: 2 Cov.: 30 AF XY: 0.000568 AC XY: 408 AN XY: 718726

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000695

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000742

Gnomad4 NFE exome AF: 0.000655

Gnomad4 OTH exome AF: 0.000565

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74358

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000533

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000975 AC: 8

ExAC AF: 0.000672 AC: 80

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000950

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the OTOGL protein (p.Arg150Trp). This variant is present in population databases (rs191608225, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 504842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Jun 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg150Trp variant in OTOGL has not been previously reported in individuals with hearing loss, but has been identified across several populations by the Ge nome Aggregation Database, including in 0.1% (115/123000) of European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs191608225). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools and conservation analyses do not provide strong support for o r against an impact to the protein. In summary, the clinical significance of the p.Arg150Trp variant is uncertain. -

Inborn genetic diseases Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.448C>T (p.R150W) alteration is located in exon 6 (coding exon 6) of the OTOGL gene. This alteration results from a C to T substitution at nucleotide position 448, causing the arginine (R) at amino acid position 150 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 84B Uncertain:1

Jul 08, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.0080	.;.;D
Sift4G	Uncertain	0.032	.;.;D
Vest4		0.39
MVP		0.35
MPC		0.084
ClinPred		0.31	T
GERP RS		5.5
gMVP		0.25

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: rs191608225; hg19: chr12-80616011;