rs202051419

Positions:

• chr12-80296918-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001378609.3(OTOGL):​c.3020T>C​(p.Val1007Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,550,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.00

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021361202).
• BP6: Variant 12-80296918-T-C is Benign according to our data. Variant chr12-80296918-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.3020T>C	p.Val1007Ala	missense_variant	27/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.3020T>C	p.Val1007Ala	missense_variant	27/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.2929-5716T>C		intron_variant				ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000184 AC: 32 AN: 173514 Hom.: 0 AF XY: 0.000183 AC XY: 17 AN XY: 92892

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000122

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000134

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.0000865 AC: 121 AN: 1398546 Hom.: 0 Cov.: 30 AF XY: 0.0000853 AC XY: 59 AN XY: 691938

Gnomad4 AFR exome AF: 0.00235

Gnomad4 AMR exome AF: 0.000391

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0000747

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000739

Gnomad4 OTH exome AF: 0.000223

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74490

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000934 Hom.: 0

Bravo AF: 0.000903

ESP6500AA AF: 0.00329 AC: 12

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000221 AC: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2015

p.Val998Ala in exon 26 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (11/2572) of African chromoso mes by the xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs202051419). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.32	T
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	.;D
Vest4		0.35
MVP		0.49
MPC		0.026
ClinPred		0.039	T
GERP RS		5.6
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs202051419; hg19: chr12-80690698; COSMIC: COSV101509456;