12-80339241-C-T

Variant names:

• chr12-80339241-C-T
• rs1477766714
• NM_001378609.3:c.5027C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378609.3(OTOGL):​c.5027C>T​(p.Ser1676Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 148,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31883085).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.5027C>T	p.Ser1676Leu	missense	Exon 43 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.5027C>T	p.Ser1676Leu	missense	Exon 46 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.5027C>T	p.Ser1676Leu	missense	Exon 43 of 59	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5027C>T	p.Ser1676Leu	missense	Exon 43 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.4892C>T	p.Ser1631Leu	missense	Exon 47 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.326C>T	p.Ser109Leu	missense	Exon 4 of 18	ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148524 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000673 AC: 1 AN: 148524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72114

African (AFR) AF: 0.0000247 AC: 1 AN: 40506

American (AMR) AF: 0.00 AC: 0 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67396

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.73	T
PhyloP100		1.6
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.22
Sift	Benign	0.30	T
Sift4G	Benign	0.24	T
Vest4		0.35
MutPred		0.55		Loss of catalytic residue at S1667 (P = 0.027)
MVP		0.40
MPC		0.026
ClinPred		0.60	D
GERP RS		4.6
gMVP		0.62
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs1477766714; hg19: chr12-80733021; COSMIC: COSV54015249; COSMIC: COSV54015249;