rs200912084

chr12-80222099-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):c.343A>C(p.Met115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,597,538 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.84

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=0.0069841444).
• BP6: Variant 12-80222099-A-C is Benign according to our data. Variant chr12-80222099-A-C is described in ClinVar as [Benign]. Clinvar id is 226938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00357 (544/152274) while in subpopulation AFR AF= 0.0125 (518/41558). AF 95% confidence interval is 0.0116. There are 6 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.343A>C	p.Met115Leu	missense_variant	7/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.343A>C	p.Met115Leu	missense_variant	7/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.343A>C	p.Met115Leu	missense_variant	12/63
OTOGL	ENST00000643417.1	n.1003A>C		non_coding_transcript_exon_variant	10/23

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152156 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000993 AC: 231 AN: 232562 Hom.: 1 AF XY: 0.000701 AC XY: 89 AN XY: 127042

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000854

GnomAD4 exome AF: 0.000367 AC: 530 AN: 1445264 Hom.: 2 Cov.: 30 AF XY: 0.000313 AC XY: 225 AN XY: 719370

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.000427

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000731

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74458

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000762 Hom.: 0

Bravo AF: 0.00407

ESP6500AA AF: 0.0106 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Met106Leu in exon 6 of OTOGL: This variant is not expected to have clinical sign ificance because it has been identified in 1.1% (39/3668) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	20
Dann	Benign	0.92
Eigen	Benign	0.11
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;.;T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
Vest4		0.23
MutPred		0.47		.;.;Loss of catalytic residue at G107 (P = 0.2074);
MVP		0.15
MPC		0.024
ClinPred		0.045	T
GERP RS		5.5
gMVP		0.12

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: rs200912084; hg19: chr12-80615879;