2-26519086-A-T

Variant names:

• chr2-26519086-A-T
• NM_194248.3:c.251T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_194248.3(OTOF):​c.251T>A​(p.Val84Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,460 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: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.66

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.251T>A	p.Val84Glu	missense_variant	Exon 4 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.251T>A	p.Val84Glu	missense_variant	Exon 4 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.251T>A	p.Val84Glu	missense_variant	Exon 4 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.251T>A	p.Val84Glu	missense_variant	Exon 4 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721768

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.98	D;.
Vest4		0.87
MutPred		0.60		Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);
MVP		0.93
MPC		0.84
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26741954;