NM_194248.3:c.2896A>T

Variant names:

• chr2-26476009-T-A
• NM_194248.3:c.2896A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194248.3(OTOF):​c.2896A>T​(p.Met966Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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: 0.0000021 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03

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=0.2550823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2896A>T	p.Met966Leu	missense_variant	Exon 24 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.655A>T	p.Met219Leu	missense_variant	Exon 7 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2896A>T	p.Met966Leu	missense_variant	Exon 24 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.655A>T	p.Met219Leu	missense_variant	Exon 7 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460456 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726520

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

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	Benign	0.21
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.10	.;.;.;T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.0064
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.24	.;.;.;N;N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;.;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.57	T;T;.;T;T;.
Sift4G	Benign	0.55	T;T;.;T;T;.
Polyphen		0.0010	B;B;.;B;.;B
Vest4		0.54
MutPred		0.59		.;.;.;Loss of MoRF binding (P = 0.0898);Loss of MoRF binding (P = 0.0898);.;
MVP		0.80
MPC		0.16
ClinPred		0.77	D
GERP RS		5.4
Varity_R		0.34
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr2-26698877;