rs7312569

Variant names:

• chr12-80353429-C-G
• rs7312569
• NM_001378609.3:c.5512C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-80353429-C-G
• chr12-80353429-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.5512C>G​(p.Leu1838Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,600,620 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2751 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27626 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.325
• Publications: 15 publications found

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]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-80353429-C-G is Benign according to our data. Variant chr12-80353429-C-G is described in ClinVar as Benign. ClinVar VariationId is 226956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5512C>G	p.Leu1838Val	missense_variant	Exon 46 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5512C>G	p.Leu1838Val	missense_variant	Exon 46 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.5377C>G	p.Leu1793Val	missense_variant	Exon 50 of 63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.811C>G	p.Leu271Val	missense_variant	Exon 7 of 18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28086 AN: 152054 Hom.: 2750 Cov.: 33

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0512

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.176 AC: 40545 AN: 229808 AF XY: 0.179

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.0441

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.191 AC: 276908 AN: 1448448 Hom.: 27626 Cov.: 30 AF XY: 0.192 AC XY: 138055 AN XY: 719156

African (AFR) AF: 0.176 AC: 5872 AN: 33276

American (AMR) AF: 0.205 AC: 8803 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4822 AN: 25846

East Asian (EAS) AF: 0.0385 AC: 1516 AN: 39390

South Asian (SAS) AF: 0.208 AC: 17415 AN: 83550

European-Finnish (FIN) AF: 0.110 AC: 5820 AN: 52912

Middle Eastern (MID) AF: 0.218 AC: 1250 AN: 5742

European-Non Finnish (NFE) AF: 0.199 AC: 220227 AN: 1104820

Other (OTH) AF: 0.187 AC: 11183 AN: 59944

GnomAD4 genome AF: 0.185 AC: 28088 AN: 152172 Hom.: 2751 Cov.: 33 AF XY: 0.182 AC XY: 13508 AN XY: 74410

African (AFR) AF: 0.181 AC: 7511 AN: 41526

American (AMR) AF: 0.215 AC: 3283 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3470

East Asian (EAS) AF: 0.0513 AC: 265 AN: 5164

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1130 AN: 10596

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13500 AN: 68000

Other (OTH) AF: 0.188 AC: 398 AN: 2112

Alfa AF: 0.190 Hom.: 2133

Bravo AF: 0.192

TwinsUK AF: 0.193 AC: 714

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.177 AC: 688

ESP6500EA AF: 0.195 AC: 1621

ExAC AF: 0.175 AC: 21080

Asia WGS AF: 0.142 AC: 491 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu1829Val in exon 45 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 19.5% (1621/8296) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs7312569). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.74	T;.;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.33
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.4	.;.;N
REVEL	Benign	0.071
Sift	Benign	0.072	.;.;T
Sift4G	Benign	0.13	.;.;T
Vest4		0.15
MPC		0.024
ClinPred		0.0015	T
GERP RS		0.45
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7312569; hg19: chr12-80747209; COSMIC: COSV54016903; COSMIC: COSV54016903;