rs76420383

Positions:

• chr12-80262069-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378609.3(OTOGL):​c.1990C>T​(p.Pro664Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,610,908 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (17 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.42

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011739701).
• BP6: Variant 12-80262069-C-T is Benign according to our data. Variant chr12-80262069-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226931.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr12-80262069-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00159 (242/152142) while in subpopulation SAS AF= 0.00686 (33/4814). AF 95% confidence interval is 0.00502. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.1990C>T	p.Pro664Ser	missense_variant	19/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.1990C>T	p.Pro664Ser	missense_variant	19/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.1990C>T	p.Pro664Ser	missense_variant	24/63
OTOGL	ENST00000643417.1	n.2650C>T		non_coding_transcript_exon_variant	22/23

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00248 AC: 609 AN: 245976 Hom.: 4 AF XY: 0.00295 AC XY: 394 AN XY: 133684

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00885

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00193 AC: 2810 AN: 1458766 Hom.: 17 Cov.: 31 AF XY: 0.00228 AC XY: 1657 AN XY: 725640

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00852

Gnomad4 FIN exome AF: 0.000938

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74374

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00686

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00140

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.00207 AC: 17

ExAC AF: 0.00266 AC: 321

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOGL: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2015	p.Pro655Ser in exon 18 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.9% (149/16498) of South Asian ch romosomes including 2 homozygotes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs76420383). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.1963C>T (p.P655S) alteration is located in exon 18 (coding exon 18) of the OTOGL gene. This alteration results from a C to T substitution at nucleotide position 1963, causing the proline (P) at amino acid position 655 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
Vest4		0.80
MVP		0.29
MPC		0.19
ClinPred		0.039	T
GERP RS		5.6
gMVP		0.74

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: rs76420383; hg19: chr12-80655849;