rs35010860

Positions:

• chr12-80377200-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.6859C>T​(p.Pro2287Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,592,074 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2287L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (216 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (185 hom.)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001550
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.88

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=0.0018273294).
• BP6: Variant 12-80377200-C-T is Benign according to our data. Variant chr12-80377200-C-T is described in ClinVar as [Benign]. Clinvar id is 226975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.6859C>T	p.Pro2287Ser	missense_variant, splice_region_variant	58/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.6859C>T	p.Pro2287Ser	missense_variant, splice_region_variant	58/59	5	NM_001378609.3	P1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4314 AN: 151960 Hom.: 216 Cov.: 32

Gnomad AFR AF: 0.0969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00749 AC: 1802 AN: 240436 Hom.: 80 AF XY: 0.00544 AC XY: 709 AN XY: 130342

Gnomad AFR exome AF: 0.0943

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000310

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000629

Gnomad OTH exome AF: 0.00511

GnomAD4 exome AF: 0.00311 AC: 4476 AN: 1439996 Hom.: 185 Cov.: 29 AF XY: 0.00268 AC XY: 1921 AN XY: 716672

Gnomad4 AFR exome AF: 0.0997

Gnomad4 AMR exome AF: 0.00652

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000288

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000310

Gnomad4 OTH exome AF: 0.00774

GnomAD4 genome AF: 0.0284 AC: 4318 AN: 152078 Hom.: 216 Cov.: 32 AF XY: 0.0275 AC XY: 2046 AN XY: 74330

Gnomad4 AFR AF: 0.0967

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00463 Hom.: 28

Bravo AF: 0.0320

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0878 AC: 387

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00914 AC: 1110

Asia WGS AF: 0.00838 AC: 29 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro2278Ser in exon 57 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 8.8% (387/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35010860). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.90
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.64	T;.;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;N;N
PrimateAI	Benign	0.28	T
Vest4		0.15
MVP		0.061
MPC		0.022
ClinPred		0.021	T
GERP RS		0.17
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.12
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: rs35010860; hg19: chr12-80770980;