rs147195954

chr12-80238893-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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. 13/17 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 Uncertain significance.

• 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:3
• 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

Verdict is Likely_benign. Variant got -5 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: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.860C>T	p.Ser287Leu	missense_variant	10/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.860C>T	p.Ser287Leu	missense_variant	10/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.860C>T	p.Ser287Leu	missense_variant	15/63
OTOGL	ENST00000643417.1	n.1520C>T		non_coding_transcript_exon_variant	13/23

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

GnomAD3 exomes AF: 0.000843 AC: 175 AN: 207580 Hom.: 0 AF XY: 0.000783 AC XY: 88 AN XY: 112402

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 SAS exome AF: 0.000185

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

Gnomad4 AMR exome AF: 0.000710

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000410

Gnomad4 FIN exome AF: 0.00121

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00119

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

Gnomad4 AMR AF: 0.000788

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00180

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00149 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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 13, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

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
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
Vest4		0.096
MVP		0.040
MPC		0.021
ClinPred		0.0098	T
GERP RS		-8.4
gMVP		0.43

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;