rs80356593

Variant names:

• chr2-26477210-G-A
• rs80356593
• NM_194248.3:c.2485C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26477210-G-A
• chr2-26477210-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP1_Strong PVS1 PP4 PM3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 22/34228) of the c.2485C>T (p.Gln829Ter) variant in the OTOF gene is 0.04% for Latino chromosomes in gnomAD v2.1.1, which meets the cutoff to apply BS1_Supporting. However, this variant has been established as a founder variant in the Spanish population and is thought to be causative in 3% of cases of deafness in the Spanish population (BS1_Supporting not applicable; PMID:27177047). The p.Gln829Ter variant in OTOF is predicted to cause a premature stop codon in biologically-relevant-exon 21/46 (NM_001287489) that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1; PMID:30192042). The p.Gln829Ter variant has been identified in >50 patients with non-syndromic hearing loss (PM3_VeryStrong; PMIDs: 18381613, 17036997, 16371502, 14635104, 12114484). It has repeatedly been reported to segregate with hearing loss (PP1_Strong; PMIDs: 12114484, 14635104,16371502, 18381613). In addition to hearing loss, at least 24 patients reported to have the p.Gln829Ter variant presented with features of auditory neuropathy spectrum disorder, which is highly specific to OTOF and autosomal recessive hearing loss (PP4; PMIDs:18381613, 17036997, 14635104). In summary, the p.Gln829Ter variant in OTOF meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PP1_Strong, PM3_VeryStrong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340525/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 4.63
• Publications: 69 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 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2485C>T	p.Gln829*	stop_gained	Exon 21 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.244C>T	p.Gln82*	stop_gained	Exon 4 of 29	NP_919304.1
	OTOF	NM_001287489.2		c.2485C>T	p.Gln829*	stop_gained	Exon 21 of 46	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2485C>T	p.Gln829*	stop_gained	Exon 21 of 47	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.244C>T	p.Gln82*	stop_gained	Exon 4 of 29	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.244C>T	p.Gln82*	stop_gained	Exon 3 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000172 AC: 42 AN: 243966 AF XY: 0.000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000643

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000665 AC: 97 AN: 1458462 Hom.: 0 Cov.: 33 AF XY: 0.0000676 AC XY: 49 AN XY: 725380

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000695 AC: 31 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111598

Other (OTH) AF: 0.0000497 AC: 3 AN: 60312

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive nonsyndromic hearing loss 9 (4)
3	-	-	not provided (3)
2	-	-	Nonsyndromic genetic hearing loss (2)
1	-	-	OTOF-related disorder (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.6
Vest4		0.90
GERP RS		5.0
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs80356593; hg19: chr2-26700078;