12-80341991-T-G

Position:

• chr12-80341991-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378609.3(OTOGL):​c.5094T>G​(p.Asn1698Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1698N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5094T>G	p.Asn1698Lys	missense_variant	44/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5094T>G	p.Asn1698Lys	missense_variant	44/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4959T>G	p.Asn1653Lys	missense_variant	48/63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.393T>G	p.Asn131Lys	missense_variant	5/18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.51	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	.;.;D
REVEL	Uncertain	0.34
Sift	Benign	0.042	.;.;D
Sift4G	Uncertain	0.0040	.;.;D
Vest4		0.68
MutPred		0.80		.;.;Gain of ubiquitination at N1689 (P = 0.0101);
MVP		0.45
MPC		0.19
ClinPred		0.98	D
GERP RS		2.7
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10778727; hg19: chr12-80735771;