rs397515588

Positions:

• chr2-26480809-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_194248.3(OTOF):​c.1780G>A​(p.Glu594Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.83

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.1780G>A	p.Glu594Lys	missense_variant	15/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.1780G>A	p.Glu594Lys	missense_variant	15/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.1780G>A	p.Glu594Lys	missense_variant	15/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.1780G>A	p.Glu594Lys	missense_variant	15/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460344 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.074	T;T
Polyphen		0.95	P;.
Vest4		0.89
MutPred		0.31		Gain of ubiquitination at E594 (P = 0.0114);Gain of ubiquitination at E594 (P = 0.0114);
MVP		0.94
MPC		0.57
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs397515588; hg19: chr2-26703677;