rs768575822

Variant names:

• chr12-80320554-A-C
• rs768575822
• NM_001378609.3:c.3935A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-80320554-A-C
• chr12-80320554-A-G
• chr12-80320554-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378609.3(OTOGL):​c.3935A>C​(p.His1312Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1312Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65
• Publications: 1 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

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.3935A>C	p.His1312Pro	missense	Exon 34 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.3935A>C	p.His1312Pro	missense	Exon 37 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.3935A>C	p.His1312Pro	missense	Exon 34 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.3935A>C	p.His1312Pro	missense	Exon 34 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.3800A>C	p.His1267Pro	missense	Exon 38 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
PhyloP100		8.7
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Vest4		0.91
MutPred		0.89		Gain of phosphorylation at T1299 (P = 0.2222)
MVP		0.29
MPC		0.21
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.88
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs768575822; hg19: chr12-80714334;