rs397515584

Positions:

• chr2-26480982-C-G
• chr2-26480982-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_194248.3(OTOF):​c.1607G>C​(p.Trp536Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.1607G>C	p.Trp536Ser	missense_variant	15/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.1607G>C	p.Trp536Ser	missense_variant	15/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.1607G>C	p.Trp536Ser	missense_variant	15/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.1607G>C	p.Trp536Ser	missense_variant	15/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460704 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-10	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.78		Loss of catalytic residue at M539 (P = 0.0022);Loss of catalytic residue at M539 (P = 0.0022);
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.84

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: rs397515584; hg19: chr2-26703850;