rs12422945

Variant names:

• chr12-80305625-A-G
• rs12422945
• NM_001378609.3:c.3263A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001378609.3(OTOGL):​c.3263A>G​(p.Asp1088Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,582,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.68
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-80305625-A-G is Benign according to our data. Variant chr12-80305625-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229116.

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.3263A>G	p.Asp1088Gly	missense	Exon 29 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.3263A>G	p.Asp1088Gly	missense	Exon 32 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.3263A>G	p.Asp1088Gly	missense	Exon 29 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.3263A>G	p.Asp1088Gly	missense	Exon 29 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.3128A>G	p.Asp1043Gly	missense	Exon 33 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

GnomAD2 exomes AF: 0.000267 AC: 60 AN: 224534 AF XY: 0.000179

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000468 AC: 67 AN: 1430636 Hom.: 0 Cov.: 29 AF XY: 0.0000337 AC XY: 24 AN XY: 711922

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.00161 AC: 66 AN: 40890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39040

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105608

Other (OTH) AF: 0.00 AC: 0 AN: 59492

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000294 AC: 35

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.54	D
PhyloP100		8.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Vest4		0.85
MutPred		0.88		Loss of stability (P = 0.0467)
MVP		0.66
MPC		0.20
ClinPred		0.45	T
GERP RS		5.9
gMVP		0.95
Mutation Taster		=23/77	disease causing

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: rs12422945; hg19: chr12-80699405;