NM_194248.3:c.5868C>A

Variant names:

• chr2-26460151-G-T
• rs727504937
• NM_194248.3:c.5868C>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.5868C>A​(p.Tyr1956*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000873 in 1,603,324 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y1956Y) 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.76
• Publications: 0 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 2-26460151-G-T is Pathogenic according to our data. Variant chr2-26460151-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2860764.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.5868C>A	p.Tyr1956*	stop_gained	Exon 46 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.3512+496C>A		intron	N/A	NP_919304.1	Q9HC10-2
	OTOF	NM_194322.3		c.3798C>A	p.Tyr1266*	stop_gained	Exon 28 of 29	NP_919303.1	Q9HC10-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5868C>A	p.Tyr1956*	stop_gained	Exon 46 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000402415.8	TSL:1	c.3627C>A	p.Tyr1209*	stop_gained	Exon 28 of 29	ENSP00000383906.4	A0A2U3TZT7
	OTOF	ENST00000338581.10	TSL:1	c.3567C>A	p.Tyr1189*	stop_gained	Exon 29 of 30	ENSP00000345137.6	Q9HC10-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000896 AC: 13 AN: 1451106 Hom.: 0 Cov.: 33 AF XY: 0.00000971 AC XY: 7 AN XY: 720550

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 43276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 84196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4824

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1107400

Other (OTH) AF: 0.00 AC: 0 AN: 60054

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		4.8
Vest4		0.66
GERP RS		4.0
Mutation Taster		=14/186	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs727504937; hg19: chr2-26683019;