NM_194248.3:c.4809C>A

Variant names:

• chr2-26465020-G-T
• rs143939430
• NM_194248.3:c.4809C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_194248.3(OTOF):​c.4809C>A​(p.Tyr1603*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y1603Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.39
• Publications: 4 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, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26465020-G-T is Pathogenic according to our data. Variant chr2-26465020-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 65805.Status of the report is criteria_provided_single_submitter, 1 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.4809C>A	p.Tyr1603*	stop_gained	Exon 39 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2508C>A	p.Tyr836*	stop_gained	Exon 22 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4809C>A	p.Tyr1603*	stop_gained	Exon 39 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4809C>A	p.Tyr1603*	stop_gained	Exon 39 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2508C>A	p.Tyr836*	stop_gained	Exon 22 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2568C>A	p.Tyr856*	stop_gained	Exon 21 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000192 AC: 32 AN: 166980 AF XY: 0.000158

Gnomad AFR exome AF: 0.000746

Gnomad AMR exome AF: 0.0000927

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000281

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000452 AC: 6 AN: 1327648 Hom.: 0 Cov.: 31 AF XY: 0.00000772 AC XY: 5 AN XY: 647922

African (AFR) AF: 0.00 AC: 0 AN: 28242

American (AMR) AF: 0.00 AC: 0 AN: 32032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35776

South Asian (SAS) AF: 0.0000638 AC: 4 AN: 62742

European-Finnish (FIN) AF: 0.0000408 AC: 2 AN: 48976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1040410

Other (OTH) AF: 0.00 AC: 0 AN: 54266

GnomAD4 genome Cov.: 32

ExAC AF: 0.000691 AC: 83

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	not provided (1)
-	-	-	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		3.4
Vest4		0.87
GERP RS		4.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143939430; hg19: chr2-26687888; COSMIC: COSV55509011;