12-80336990-C-G

Position:

• chr12-80336990-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378609.3(OTOGL):​c.4846C>G​(p.Arg1616Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,428,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.97

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.4846C>G	p.Arg1616Gly	missense_variant	42/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.4846C>G	p.Arg1616Gly	missense_variant	42/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1	c.4711C>G	p.Arg1571Gly	missense_variant	46/63			ENSP00000496036
OTOGL	ENST00000298820.7	c.148C>G	p.Arg50Gly	missense_variant	3/18	5		ENSP00000298820

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000505 AC: 1 AN: 198178 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000338

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: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000244

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	0.62	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.1	.;.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	.;.;D
Sift4G	Pathogenic	0.0	.;.;D
Vest4		0.89
MutPred		0.68		.;.;Loss of MoRF binding (P = 0.0354);
MVP		0.44
MPC		0.20
ClinPred		0.97	D
GERP RS		2.9
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs536538111; hg19: chr12-80730770;