NM_194248.3:c.245G>T

Variant names:

• chr2-26519092-C-A
• rs149766574
• NM_194248.3:c.245G>T

Variant summary

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

The NM_194248.3(OTOF):​c.245G>T​(p.Arg82Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82C) has been classified as Benign.

• 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: 3.68

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.245G>T	p.Arg82Leu	missense_variant	Exon 4 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.245G>T	p.Arg82Leu	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.245G>T	p.Arg82Leu	missense_variant	Exon 4 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.245G>T	p.Arg82Leu	missense_variant	Exon 4 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450858 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720780

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: 9.05e-7

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	Benign	0.17
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.084	T;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.15
Sift	Benign	0.47	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.13	B;.
Vest4		0.65
MutPred		0.48		Loss of MoRF binding (P = 0.0203);Loss of MoRF binding (P = 0.0203);
MVP		0.87
MPC		0.29
ClinPred		0.86	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149766574; hg19: chr2-26741960;