NM_001378609.3:c.3020T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001378609.3(OTOGL):​c.3020T>C​(p.Val1007Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,550,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1007F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

8
8

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.00

Publications

2 publications found
Variant links:
Genes affected
OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]
OTOGL Gene-Disease associations (from GenCC):
  • autosomal recessive nonsyndromic hearing loss 84B
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • 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: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.021361202).
BP6
Variant 12-80296918-T-C is Benign according to our data. Variant chr12-80296918-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000702 (107/152328) while in subpopulation AFR AF = 0.00231 (96/41572). AF 95% confidence interval is 0.00194. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOGLNM_001378609.3 linkc.3020T>C p.Val1007Ala missense_variant Exon 27 of 59 ENST00000547103.7 NP_001365538.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOGLENST00000547103.7 linkc.3020T>C p.Val1007Ala missense_variant Exon 27 of 59 5 NM_001378609.3 ENSP00000447211.2 Q3ZCN5
OTOGLENST00000646859.1 linkc.2929-5716T>C intron_variant Intron 31 of 62 ENSP00000496036.1 A0A2R8YF04

Frequencies

GnomAD3 genomes
AF:
0.000703
AC:
107
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00232
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD2 exomes
AF:
0.000184
AC:
32
AN:
173514
AF XY:
0.000183
show subpopulations
Gnomad AFR exome
AF:
0.00169
Gnomad AMR exome
AF:
0.000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000134
Gnomad OTH exome
AF:
0.000209
GnomAD4 exome
AF:
0.0000865
AC:
121
AN:
1398546
Hom.:
0
Cov.:
30
AF XY:
0.0000853
AC XY:
59
AN XY:
691938
show subpopulations
African (AFR)
AF:
0.00235
AC:
77
AN:
32700
American (AMR)
AF:
0.000391
AC:
15
AN:
38338
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25326
East Asian (EAS)
AF:
0.0000260
AC:
1
AN:
38390
South Asian (SAS)
AF:
0.0000747
AC:
6
AN:
80302
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
36452
Middle Eastern (MID)
AF:
0.000176
AC:
1
AN:
5672
European-Non Finnish (NFE)
AF:
0.00000739
AC:
8
AN:
1083028
Other (OTH)
AF:
0.000223
AC:
13
AN:
58338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.457
Heterozygous variant carriers
0
5
11
16
22
27
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.000702
AC:
107
AN:
152328
Hom.:
0
Cov.:
33
AF XY:
0.000644
AC XY:
48
AN XY:
74490
show subpopulations
African (AFR)
AF:
0.00231
AC:
96
AN:
41572
American (AMR)
AF:
0.000457
AC:
7
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.000947
AC:
2
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
5
10
16
21
26
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:
0.000250
Hom.:
0
Bravo
AF:
0.000903
ESP6500AA
AF:
0.00329
AC:
12
ESP6500EA
AF:
0.000123
AC:
1
ExAC
AF:
0.000221
AC:
26

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Jul 20, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Val998Ala in exon 26 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (11/2572) of African chromoso mes by the xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs202051419). -

Inborn genetic diseases Benign:1
Feb 27, 2024
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1
Feb 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Uncertain
1.0
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.59
.;T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.021
T;T
MetaSVM
Benign
-0.32
T
PhyloP100
5.0
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-3.4
.;D
REVEL
Uncertain
0.31
Sift
Uncertain
0.0010
.;D
Sift4G
Uncertain
0.0030
.;D
Vest4
0.35
MVP
0.49
MPC
0.026
ClinPred
0.039
T
GERP RS
5.6
gMVP
0.57
Mutation Taster
=52/48
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs202051419; hg19: chr12-80690698; COSMIC: COSV101509456; API