rs756143591

chr2-26516539-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_194248.3(OTOF):c.388G>A(p.Asp130Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D130D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32036382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.388G>A	p.Asp130Asn	missense_variant	5/47	ENST00000272371.7
OTOF	NM_001287489.2	c.388G>A	p.Asp130Asn	missense_variant	5/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.388G>A	p.Asp130Asn	missense_variant	5/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.388G>A	p.Asp130Asn	missense_variant	5/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135444

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460548 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726676

Gnomad4 AFR exome AF: 0.0000597

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 12, 2015

The p.Asp130Asn variant in OTOF has not been previously reported in any individu al with hearing loss, but has been identified in 1/10307 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analyses do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the Asp130Asn variant is uncert ain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.20
Sift	Benign	0.27	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0020	B;.
Vest4		0.49
MutPred		0.32		Loss of phosphorylation at S127 (P = 0.1056);Loss of phosphorylation at S127 (P = 0.1056);
MVP		0.81
MPC		0.30
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.053
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs756143591; hg19: chr2-26739407; COSMIC: COSV99716408;