chr2-26467364-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_194248.3(OTOF):​c.4227+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000868 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

OTOF
NM_194248.3 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 5.49

Publications

4 publications found
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]
OTOF Gene-Disease associations (from GenCC):
  • autosomal recessive nonsyndromic hearing loss 9
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.5, offset of 29, new splice context is: aggGTgtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP5
Variant 2-26467364-C-A is Pathogenic according to our data. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26467364-C-A is described in CliVar as Pathogenic. Clinvar id is 65802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOFNM_194248.3 linkc.4227+1G>T splice_donor_variant, intron_variant Intron 34 of 46 ENST00000272371.7 NP_919224.1 Q9HC10-1
OTOFNM_194323.3 linkc.1926+1G>T splice_donor_variant, intron_variant Intron 17 of 28 ENST00000339598.8 NP_919304.1 Q9HC10-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOFENST00000272371.7 linkc.4227+1G>T splice_donor_variant, intron_variant Intron 34 of 46 1 NM_194248.3 ENSP00000272371.2 Q9HC10-1
OTOFENST00000339598.8 linkc.1926+1G>T splice_donor_variant, intron_variant Intron 17 of 28 1 NM_194323.3 ENSP00000344521.3 Q9HC10-2

Frequencies

GnomAD3 genomes
AF:
0.0000790
AC:
12
AN:
151994
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251414
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461750
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727172
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53276
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000790
AC:
12
AN:
151994
Hom.:
0
Cov.:
32
AF XY:
0.0000943
AC XY:
7
AN XY:
74202
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41372
American (AMR)
AF:
0.000720
AC:
11
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5158
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4786
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68004
Other (OTH)
AF:
0.000479
AC:
1
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:1Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Feb 26, 2019
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:case-control

- -

not provided Pathogenic:1
Jan 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects a donor splice site in intron 34 of the OTOF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is present in population databases (rs397515601, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with deafness (PMID: 18381613). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 65802). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
PhyloP100
5.5
GERP RS
4.3
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.48
Position offset: 2
DS_DL_spliceai
1.0
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs397515601; hg19: chr2-26690232; API