rs139201321

Variant names:

• chr2-26464878-C-A
• NM_194248.3:c.4951G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26464878-C-A
• chr2-26464878-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.4951G>T​(p.Asp1651Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,760 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4951G>T	p.Asp1651Tyr	missense_variant	Exon 39 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2650G>T	p.Asp884Tyr	missense_variant	Exon 22 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4951G>T	p.Asp1651Tyr	missense_variant	Exon 39 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2650G>T	p.Asp884Tyr	missense_variant	Exon 22 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450760 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721038

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;.;.;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.8	.;.;.;M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D;D;.;D;D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D;D;.;D;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.88
MutPred		0.35		.;.;.;Gain of phosphorylation at D1651 (P = 0.0073);Gain of phosphorylation at D1651 (P = 0.0073);.;
MVP		0.82
MPC		0.73
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26687746;