rs147195954

Variant names:

• chr12-80238893-C-T
• rs147195954
• NM_001378609.3:c.860C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378609.3(OTOGL):​c.860C>T​(p.Ser287Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,579,910 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S287S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0770

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009349346).
• BP6: Variant 12-80238893-C-T is Benign according to our data. Variant chr12-80238893-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504844.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.860C>T	p.Ser287Leu	missense_variant	Exon 10 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.860C>T	p.Ser287Leu	missense_variant	Exon 10 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.860C>T	p.Ser287Leu	missense_variant	Exon 15 of 63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.1520C>T		non_coding_transcript_exon_variant	Exon 13 of 23

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 151856 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000843 AC: 175 AN: 207580 AF XY: 0.000783

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000917

GnomAD4 exome AF: 0.00136 AC: 1937 AN: 1427938 Hom.: 3 Cov.: 32 AF XY: 0.00128 AC XY: 910 AN XY: 708560

Gnomad4 AFR exome AF: 0.000301 AC: 10 AN: 33172

Gnomad4 AMR exome AF: 0.000710 AC: 30 AN: 42272

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25762

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39070

Gnomad4 SAS exome AF: 0.000410 AC: 34 AN: 82990

Gnomad4 FIN exome AF: 0.00121 AC: 46 AN: 38086

Gnomad4 NFE exome AF: 0.00158 AC: 1744 AN: 1101272

Gnomad4 Remaining exome AF: 0.00119 AC: 71 AN: 59568

GnomAD4 genome AF: 0.00112 AC: 170 AN: 151972 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74264

Gnomad4 AFR AF: 0.000482 AC: 0.000482253 AN: 0.000482253

Gnomad4 AMR AF: 0.000788 AC: 0.000788022 AN: 0.000788022

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000832 AC: 0.000831601 AN: 0.000831601

Gnomad4 FIN AF: 0.00180 AC: 0.00179992 AN: 0.00179992

Gnomad4 NFE AF: 0.00168 AC: 0.00167726 AN: 0.00167726

Gnomad4 OTH AF: 0.000474 AC: 0.000473934 AN: 0.000473934

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000929

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00132 AC: 11

ExAC AF: 0.000714 AC: 85

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Dec 20, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser278Leu in exon 9 of OTOGL: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, over 10 mammalian species have a Leu at this position despite high nearby a mino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. The variant has also been reporte d in 0.13% (152/108892) of European chromosomes by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147195954). -

Inborn genetic diseases Benign:1

Oct 29, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.73
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T;.;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0093	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Benign	0.060
Sift	Benign	0.37	.;.;T
Sift4G	Benign	0.42	.;.;T
Vest4		0.096
MVP		0.040
MPC		0.021
ClinPred		0.0098	T
GERP RS		-8.4
gMVP		0.43
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147195954; hg19: chr12-80632673; COSMIC: COSV72005624;