rs80356605

Variant names:

• chr2-26460203-C-A
• rs80356605
• NM_194248.3:c.5816G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26460203-C-A
• chr2-26460203-C-G
• chr2-26460203-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_194248.3(OTOF):​c.5816G>T​(p.Arg1939Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1939W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• 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 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26460204-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65813.

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.5816G>T	p.Arg1939Leu	missense splice_region	Exon 46 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.3512+444G>T		intron	N/A	NP_919304.1
	OTOF	NM_194322.3		c.3746G>T	p.Arg1249Leu	missense splice_region	Exon 28 of 29	NP_919303.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.5816G>T	p.Arg1939Leu	missense splice_region	Exon 46 of 47	ENSP00000272371.2
	OTOF	ENST00000402415.8	TSL:1	c.3575G>T	p.Arg1192Leu	missense splice_region	Exon 28 of 29	ENSP00000383906.4
	OTOF	ENST00000338581.10	TSL:1	c.3515G>T	p.Arg1172Leu	missense splice_region	Exon 29 of 30	ENSP00000345137.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.6
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.61		Gain of catalytic residue at R1939 (P = 0.0245)
MVP		0.89
MPC		0.55
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.96
gMVP		0.95
Mutation Taster		=30/70	disease causing

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: rs80356605; hg19: chr2-26683071;