rs112430701

Positions:

• chr12-80271680-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001378609.3(OTOGL):​c.2551G>A​(p.Asp851Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,612,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.77

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014784217).
• BP6: Variant 12-80271680-G-A is Benign according to our data. Variant chr12-80271680-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227817.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.2551G>A	p.Asp851Asn	missense_variant	24/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.2551G>A	p.Asp851Asn	missense_variant	24/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.2551G>A	p.Asp851Asn	missense_variant	29/63

Frequencies

GnomAD3 genomes AF: 0.000639 AC: 97 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000146 AC: 36 AN: 245858 Hom.: 0 AF XY: 0.0000823 AC XY: 11 AN XY: 133598

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000727

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 193 AN: 1460776 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 726676

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000638 AC: 97 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74298

Gnomad4 AFR AF: 0.00215

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000582

ESP6500AA AF: 0.00182 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 24

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 22, 2015

p.Asp842Asn in exon 23 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (20/9728) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs112430701) and due to a lack of conservation across species, including ma mmals. Of note, bat, microbat, and big brown bat have an asparagine (Asn) at thi s position despite high nearby amino acid conservation. In addition, computation al prediction tools suggest that the p.Asp842Asn variant may not impact the prot ein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Benign	0.50
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.45	T
Vest4		0.30
MVP		0.27
MPC		0.033
ClinPred		0.050	T
GERP RS		4.5
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112430701; hg19: chr12-80665460; COSMIC: COSV101509547;