chr12-80262054-G-A

Position:

• chr12-80262054-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.1975G>A​(p.Val659Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,612,654 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (109 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (107 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.19

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026710331).
• BP6: Variant 12-80262054-G-A is Benign according to our data. Variant chr12-80262054-G-A is described in ClinVar as [Benign]. Clinvar id is 226930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.1975G>A	p.Val659Ile	missense_variant	19/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.1975G>A	p.Val659Ile	missense_variant	19/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.1975G>A	p.Val659Ile	missense_variant	24/63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.2635G>A		non_coding_transcript_exon_variant	22/23

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3139 AN: 152120 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00552 AC: 1359 AN: 246362 Hom.: 53 AF XY: 0.00418 AC XY: 559 AN XY: 133868

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00220 AC: 3210 AN: 1460416 Hom.: 107 Cov.: 31 AF XY: 0.00195 AC XY: 1420 AN XY: 726470

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.00415

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.0206 AC: 3141 AN: 152238 Hom.: 109 Cov.: 33 AF XY: 0.0197 AC XY: 1467 AN XY: 74430

Gnomad4 AFR AF: 0.0708

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00372 Hom.: 28

Bravo AF: 0.0239

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0633 AC: 240

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00670 AC: 810

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Val650Ile in exon 18 of OTOGL: This variant is not expected to have clinical sig nificance because it has been identified in 6.3% (240/3792) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs76258355). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T;.;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.31	.;.;N
REVEL	Benign	0.088
Sift	Benign	0.50	.;.;T
Sift4G	Benign	0.56	.;.;T
Vest4		0.17
MVP		0.067
MPC		0.024
ClinPred		0.017	T
GERP RS		5.6
gMVP		0.21

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: rs76258355; hg19: chr12-80655834;