2-26516539-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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. 13/21 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

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
OTOFNM_194248.3 linkc.388G>A p.Asp130Asn missense_variant Exon 5 of 47 ENST00000272371.7 NP_919224.1 Q9HC10-1
OTOFNM_001287489.2 linkc.388G>A p.Asp130Asn missense_variant Exon 5 of 46 NP_001274418.1 Q9HC10-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOFENST00000272371.7 linkc.388G>A p.Asp130Asn missense_variant Exon 5 of 47 1 NM_194248.3 ENSP00000272371.2 Q9HC10-1
OTOFENST00000403946.7 linkc.388G>A p.Asp130Asn missense_variant Exon 5 of 46 5 ENSP00000385255.3 Q9HC10-5

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 12, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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