NM_194248.3:c.3239G>C

Variant names:

• chr2-26474562-C-G
• rs397515598
• NM_194248.3:c.3239G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_194248.3(OTOF):​c.3239G>C​(p.Arg1080Pro) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1080H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 6.13
• Publications: 12 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 2-26474562-C-G is Pathogenic according to our data. Variant chr2-26474562-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 65796.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3239G>C	p.Arg1080Pro	missense_variant	Exon 26 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.998G>C	p.Arg333Pro	missense_variant	Exon 9 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3239G>C	p.Arg1080Pro	missense_variant	Exon 26 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.998G>C	p.Arg333Pro	missense_variant	Exon 9 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral sensorineural hearing impairment Pathogenic:1

-

Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

in compound heterozygosis with another missense variant, both likely pathogenic in patient with auditory neuropathy -

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	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;.;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Uncertain	2.4	.;.;.;M;M;.
PhyloP100		6.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	D;D;.;D;D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.084	T;T;.;T;T;.
Sift4G	Benign	0.087	T;T;.;T;T;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.78
MutPred		0.81		.;.;.;Loss of solvent accessibility (P = 0.0703);Loss of solvent accessibility (P = 0.0703);.;
MVP		0.92
MPC		0.79
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.90
Mutation Taster		=0/100	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: rs397515598; hg19: chr2-26697430;