rs1553352609

Positions:

• chr2-26477172-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 1302777.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP3: Splicing scoreres supports a deletorius 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/exons	MANE	UniProt
OTOF	NM_194248.3	c.2523G>T	p.Glu841Asp	missense_variant, splice_region_variant	21/47	ENST00000272371.7
OTOF	NM_194323.3	c.282G>T	p.Glu94Asp	missense_variant, splice_region_variant	4/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2523G>T	p.Glu841Asp	missense_variant, splice_region_variant	21/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.282G>T	p.Glu94Asp	missense_variant, splice_region_variant	4/29	1	NM_194323.3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2017

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;.
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

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