NM_194248.3:c.2348delG

Variant names:

• chr2-26477473-GC-G
• rs80356591
• NM_194248.3:c.2348delG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_194248.3(OTOF):​c.2348delG​(p.Gly783AlafsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,603,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: OTOF NM_194248.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 2.21
• Publications: 7 publications found

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-26477473-GC-G is Pathogenic according to our data. Variant chr2-26477473-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 21834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. 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
	OTOF	NM_194248.3	MANE Select	c.2348delG	p.Gly783AlafsTer17	frameshift	Exon 20 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.107delG	p.Gly36AlafsTer17	frameshift	Exon 3 of 29	NP_919304.1
	OTOF	NM_001287489.2		c.2348delG	p.Gly783AlafsTer17	frameshift	Exon 20 of 46	NP_001274418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2348delG	p.Gly783AlafsTer17	frameshift	Exon 20 of 47	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.107delG	p.Gly36AlafsTer17	frameshift	Exon 3 of 29	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.107delG	p.Gly36AlafsTer17	frameshift	Exon 2 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000390 AC: 9 AN: 230852 AF XY: 0.0000240

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000675

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1451656 Hom.: 0 Cov.: 33 AF XY: 0.0000915 AC XY: 66 AN XY: 720996

African (AFR) AF: 0.0000899 AC: 3 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 43486

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 84304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1108042

Other (OTH) AF: 0.000100 AC: 6 AN: 60024

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74296

African (AFR) AF: 0.0000966 AC: 4 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000110

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 9 (2)
1	-	-	Bilateral sensorineural hearing impairment (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs80356591; hg19: chr2-26700341;