12-80356879-G-C

Variant names:

• chr12-80356879-G-C
• rs11836060
• NM_001378609.3:c.5984G>C

Variant summary

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

The NM_001378609.3(OTOGL):​c.5984G>C​(p.Arg1995Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1995Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89
• Publications: 15 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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=0.32281297).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.5984G>C	p.Arg1995Pro	missense	Exon 49 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5984G>C	p.Arg1995Pro	missense	Exon 52 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5984G>C	p.Arg1995Pro	missense	Exon 49 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5984G>C	p.Arg1995Pro	missense	Exon 49 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.5849G>C	p.Arg1950Pro	missense	Exon 53 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1283G>C	p.Arg428Pro	missense	Exon 10 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151722 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1 AN: 151722 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41264

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 9095

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.029
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.95	T
PhyloP100		3.9
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Vest4		0.36
MVP		0.21
MPC		0.043
ClinPred		0.94	D
GERP RS		4.1
gMVP		0.76
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs11836060; hg19: chr12-80750659;