rs1553352609

Variant names:

• chr2-26477172-C-A
• rs1553352609
• NM_194248.3:c.2523G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_194248.3(OTOF):​c.2523G>T​(p.Glu841Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E841K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26477174-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1302777.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2523G>T	p.Glu841Asp	missense_variant, splice_region_variant	Exon 21 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.282G>T	p.Glu94Asp	missense_variant, splice_region_variant	Exon 4 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2523G>T	p.Glu841Asp	missense_variant, splice_region_variant	Exon 21 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.282G>T	p.Glu94Asp	missense_variant, splice_region_variant	Exon 4 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu841Asp variant in OTOF has not been previously reported in individuals with hearing lo ss and was absent from large population studies. This variant is located at the last base of the exon, which is part of the 5? splice region. Computational tool s suggest an impact to splicing; however, this information is not predictive eno ugh to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu841Asp variant is uncerta in. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;.;.;T;.;.
Eigen	Benign	0.0088
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.8	.;.;.;L;L;.
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.53	N;N;.;N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.26	T;T;.;T;T;.
Sift4G	Benign	0.23	T;T;.;T;T;.
Polyphen		0.018	B;B;.;B;.;B
Vest4		0.57
MutPred		0.35		.;.;.;Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.90
MPC		0.21
ClinPred		0.66	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.70
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553352609; hg19: chr2-26700040; COSMIC: COSV55519365; COSMIC: COSV55519365;