rs143817729

chr12-80339120-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378609.3(OTOGL):c.4906G>A(p.Glu1636Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00204 in 1,611,698 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.22

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00897333).
• BP6: Variant 12-80339120-G-A is Benign according to our data. Variant chr12-80339120-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.4906G>A	p.Glu1636Lys	missense_variant	43/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.4906G>A	p.Glu1636Lys	missense_variant	43/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.4771G>A	p.Glu1591Lys	missense_variant	47/63
OTOGL	ENST00000298820.7	c.208G>A	p.Glu70Lys	missense_variant	4/18	5

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 206 AN: 151760 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00165 AC: 407 AN: 246378 Hom.: 2 AF XY: 0.00170 AC XY: 227 AN XY: 133900

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00211 AC: 3075 AN: 1459820 Hom.: 5 Cov.: 32 AF XY: 0.00207 AC XY: 1506 AN XY: 726298

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00582

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00135 AC: 205 AN: 151878 Hom.: 3 Cov.: 32 AF XY: 0.00127 AC XY: 94 AN XY: 74250

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00491

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.00200 Hom.: 2

Bravo AF: 0.00154

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000269 AC: 1

ESP6500EA AF: 0.00135 AC: 11

ExAC AF: 0.00166 AC: 200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	OTOGL: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2015

p.Glu1627Lys in exon 42 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 0.3% (39/11552) of Latino chromos omes and 0.23% (155/66672) European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs143817729). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

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	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Vest4		0.22
MVP		0.38
MPC		0.027
ClinPred		0.018	T
GERP RS		5.7
gMVP		0.59

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: rs143817729; hg19: chr12-80732900;