12-80211953-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001378609.3(OTOGL):c.124G>A(p.Gly42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000079 in 1,569,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.56

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-80211953-G-A is Benign according to our data. Variant chr12-80211953-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1211910.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.124G>A	p.Gly42Arg	missense_variant	4/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.124G>A	p.Gly42Arg	missense_variant	4/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.124G>A	p.Gly42Arg	missense_variant	9/63
OTOGL	ENST00000643417.1	n.784G>A		non_coding_transcript_exon_variant	7/23

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000790 AC: 15 AN: 189892 Hom.: 0 AF XY: 0.0000684 AC XY: 7 AN XY: 102302

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.0000339

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: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000381 AC: 54 AN: 1417324 Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 27 AN XY: 702146

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.0000497

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74458

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000474 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.000546 AC: 2

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000676 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 33 of the OTOGL protein (p.Gly33Arg). This variant is present in population databases (rs149117887, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1211910). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.97G>A (p.G33R) alteration is located in exon 3 (coding exon 3) of the OTOGL gene. This alteration results from a G to A substitution at nucleotide position 97, causing the glycine (G) at amino acid position 33 to be replaced by an arginine (R). 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	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	-0.095
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.49	T;.;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
Vest4		0.29
MutPred		0.17		.;.;Gain of MoRF binding (P = 0.05);
MVP		0.16
MPC		0.024
ClinPred		0.030	T
GERP RS		3.7
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 2
DS_AL_spliceai		0.22		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs149117887; hg19: chr12-80605733;