rs200283244

chr2-26464907-C-Achr2-26464907-C-T

Variant summary

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

The NM_194248.3(OTOF):c.4922G>T(p.Arg1641Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,597,354 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1641H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14

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/exons	MANE	UniProt
OTOF	NM_194248.3	c.4922G>T	p.Arg1641Leu	missense_variant	39/47	ENST00000272371.7
OTOF	NM_194323.3	c.2621G>T	p.Arg874Leu	missense_variant	22/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4922G>T	p.Arg1641Leu	missense_variant	39/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2621G>T	p.Arg874Leu	missense_variant	22/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1445214 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D;D;.;D;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D;D;.;D;D;.
Sift4G	Uncertain	0.012	D;D;.;D;D;.
Polyphen		0.77	P;P;.;B;.;B
Vest4		0.83
MutPred		0.50		.;.;.;Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);.;
MVP		0.86
MPC		0.47
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.75

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: rs200283244; hg19: chr2-26687775;