rs150426222

chr12-80310633-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001378609.3(OTOGL):c.3356T>C(p.Ile1119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,593,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (6 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.09

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008200735).
• BP6: Variant 12-80310633-T-C is Benign according to our data. Variant chr12-80310633-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226941.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=2}. Variant chr12-80310633-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00192 (293/152342) while in subpopulation AFR AF= 0.00452 (188/41584). AF 95% confidence interval is 0.00399. There are 0 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.3356T>C	p.Ile1119Thr	missense_variant	30/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.3356T>C	p.Ile1119Thr	missense_variant	30/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.3221T>C	p.Ile1074Thr	missense_variant	34/63

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00108 AC: 254 AN: 234348 Hom.: 1 AF XY: 0.00105 AC XY: 134 AN XY: 128078

Gnomad AFR exome AF: 0.00422

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000889

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.000744 AC: 1072 AN: 1440710 Hom.: 6 Cov.: 30 AF XY: 0.000739 AC XY: 530 AN XY: 717540

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000511

Gnomad4 NFE exome AF: 0.000539

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74496

Gnomad4 AFR AF: 0.00452

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.00223

ESP6500AA AF: 0.00356 AC: 13

ESP6500EA AF: 0.000613 AC: 5

ExAC AF: 0.000975 AC: 116

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00113

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ile1110Thr in exon 29 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 4.6% (9/194) of Luhya (Kenyan) chro mosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm .nih.gov/projects/SNP; dbSNP rs150426222). -

OTOGL-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	18
Dann	Benign	0.91
Eigen	Benign	0.029
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.30	T
Vest4		0.14
MVP		0.048
MPC		0.024
ClinPred		0.011	T
GERP RS		5.9
gMVP		0.25

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: rs150426222; hg19: chr12-80704413;