rs121908598

Variant names:

• chr2-26458074-G-C
• rs121908598
• NM_194323.3:c.3659C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_194323.3(OTOF):​c.3659C>G​(p.Pro1220Arg) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194323.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.90
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 2-26458074-G-C is Pathogenic according to our data. Variant chr2-26458074-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6141.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194323.3. 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_194323.3	MANE Plus Clinical	c.3659C>G	p.Pro1220Arg	missense	Exon 29 of 29	NP_919304.1
	OTOF	NM_194248.3	MANE Select	c.*164C>G		3_prime_UTR	Exon 47 of 47	NP_919224.1
	OTOF	NM_001287489.2		c.5960C>G	p.Pro1987Arg	missense	Exon 46 of 46	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.3659C>G	p.Pro1220Arg	missense	Exon 29 of 29	ENSP00000344521.3
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.*164C>G		3_prime_UTR	Exon 47 of 47	ENSP00000272371.2
	OTOF	ENST00000402415.8	TSL:1	c.*164C>G		3_prime_UTR	Exon 29 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Auditory neuropathy, autosomal recessive, 1 Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.93	D
PhyloP100		9.9
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.45		Loss of loop (P = 0.0073)
MVP		0.97
ClinPred		0.99	D
GERP RS		4.8
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs121908598; hg19: chr2-26680942;