rs80356579

chr2-26464956-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_194248.3(OTOF):c.4873G>A(p.Val1625Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.83

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29857415).
• BP6: Variant 2-26464956-C-T is Benign according to our data. Variant chr2-26464956-C-T is described in ClinVar as [Benign]. Clinvar id is 21855.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4873G>A	p.Val1625Met	missense_variant	39/47	ENST00000272371.7
OTOF	NM_194323.3	c.2572G>A	p.Val858Met	missense_variant	22/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4873G>A	p.Val1625Met	missense_variant	39/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2572G>A	p.Val858Met	missense_variant	22/29	1	NM_194323.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Benign, no assertion criteria provided

curation

GeneReviews

Apr 26, 2011

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	0.96	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.78	N;N;.;N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0040	D;D;.;D;D;.
Sift4G	Uncertain	0.016	D;D;.;D;D;.
Polyphen		0.67	P;P;.;P;.;P
Vest4		0.56
MutPred		0.21		.;.;.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;
MVP		0.86
MPC		0.47
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.094
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356579; hg19: chr2-26687824;