NM_194248.3:c.3032T>C

Variant names:

• chr2-26475453-A-G
• rs80356596
• NM_194248.3:c.3032T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_194248.3(OTOF):​c.3032T>C​(p.Leu1011Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L1011L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.27
• Publications: 16 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 2-26475453-A-G is Pathogenic according to our data. Variant chr2-26475453-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6142.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3032T>C	p.Leu1011Pro	missense_variant	Exon 25 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.791T>C	p.Leu264Pro	missense_variant	Exon 8 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3032T>C	p.Leu1011Pro	missense_variant	Exon 25 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.791T>C	p.Leu264Pro	missense_variant	Exon 8 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Auditory neuropathy, autosomal recessive, 1 Pathogenic:1

Sep 15, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal recessive nonsyndromic hearing loss 9 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.4	.;.;.;M;M;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D;.;D;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.99
MutPred		0.92		.;.;.;Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);.;
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80356596; hg19: chr2-26698321;