NM_206933.4:c.9343A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):​c.9343A>G​(p.Thr3115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 1,613,802 control chromosomes in the GnomAD database, including 2,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 168 hom., cov: 32)
Exomes 𝑓: 0.049 ( 2363 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0680

Publications

28 publications found
Variant links:
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
USH2A Gene-Disease associations (from GenCC):
  • Usher syndrome type 2
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Usher syndrome type 2A
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • retinitis pigmentosa 39
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • retinitis pigmentosa
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.001318723).
BP6
Variant 1-215838019-T-C is Benign according to our data. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in CliVar as Benign. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.9343A>G p.Thr3115Ala missense_variant Exon 47 of 72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.9343A>G p.Thr3115Ala missense_variant Exon 47 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.9343A>G p.Thr3115Ala missense_variant Exon 47 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0361
AC:
5492
AN:
152178
Hom.:
169
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0101
Gnomad AMI
AF:
0.0197
Gnomad AMR
AF:
0.0540
Gnomad ASJ
AF:
0.00865
Gnomad EAS
AF:
0.152
Gnomad SAS
AF:
0.0769
Gnomad FIN
AF:
0.00659
Gnomad MID
AF:
0.0443
Gnomad NFE
AF:
0.0421
Gnomad OTH
AF:
0.0439
GnomAD2 exomes
AF:
0.0497
AC:
12498
AN:
251308
AF XY:
0.0504
show subpopulations
Gnomad AFR exome
AF:
0.00886
Gnomad AMR exome
AF:
0.0580
Gnomad ASJ exome
AF:
0.00804
Gnomad EAS exome
AF:
0.169
Gnomad FIN exome
AF:
0.00795
Gnomad NFE exome
AF:
0.0373
Gnomad OTH exome
AF:
0.0413
GnomAD4 exome
AF:
0.0490
AC:
71657
AN:
1461506
Hom.:
2363
Cov.:
31
AF XY:
0.0496
AC XY:
36036
AN XY:
727078
show subpopulations
African (AFR)
AF:
0.00812
AC:
272
AN:
33478
American (AMR)
AF:
0.0579
AC:
2591
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00831
AC:
217
AN:
26126
East Asian (EAS)
AF:
0.151
AC:
5985
AN:
39670
South Asian (SAS)
AF:
0.0805
AC:
6939
AN:
86244
European-Finnish (FIN)
AF:
0.00927
AC:
495
AN:
53418
Middle Eastern (MID)
AF:
0.0317
AC:
183
AN:
5768
European-Non Finnish (NFE)
AF:
0.0464
AC:
51635
AN:
1111700
Other (OTH)
AF:
0.0553
AC:
3340
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.461
Heterozygous variant carriers
0
3387
6775
10162
13550
16937
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2110
4220
6330
8440
10550
<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:
0.0360
AC:
5486
AN:
152296
Hom.:
168
Cov.:
32
AF XY:
0.0364
AC XY:
2714
AN XY:
74468
show subpopulations
African (AFR)
AF:
0.0101
AC:
420
AN:
41576
American (AMR)
AF:
0.0538
AC:
822
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00865
AC:
30
AN:
3470
East Asian (EAS)
AF:
0.152
AC:
787
AN:
5180
South Asian (SAS)
AF:
0.0768
AC:
371
AN:
4832
European-Finnish (FIN)
AF:
0.00659
AC:
70
AN:
10620
Middle Eastern (MID)
AF:
0.0374
AC:
11
AN:
294
European-Non Finnish (NFE)
AF:
0.0421
AC:
2862
AN:
68022
Other (OTH)
AF:
0.0449
AC:
95
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
272
543
815
1086
1358
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
70
140
210
280
350
<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:
0.0419
Hom.:
587
Bravo
AF:
0.0371
TwinsUK
AF:
0.0496
AC:
184
ALSPAC
AF:
0.0420
AC:
162
ESP6500AA
AF:
0.0123
AC:
54
ESP6500EA
AF:
0.0398
AC:
342
ExAC
AF:
0.0487
AC:
5917
Asia WGS
AF:
0.112
AC:
387
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Jun 24, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 06, 2014
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2Other:1
-
NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Usher syndrome type 2A Benign:2
Sep 16, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 01, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Retinal dystrophy Benign:1
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.78
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
2.7
DANN
Benign
0.44
DEOGEN2
Benign
0.031
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.079
N
LIST_S2
Benign
0.43
T
MetaRNN
Benign
0.0013
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.90
L
PhyloP100
0.068
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.48
N
REVEL
Benign
0.14
Sift
Benign
0.79
T
Sift4G
Benign
0.72
T
Polyphen
0.0
B
Vest4
0.053
MPC
0.030
ClinPred
0.0032
T
GERP RS
-5.6
Varity_R
0.034
gMVP
0.20
Mutation Taster
=88/12
polymorphism (auto)

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

Other links and lift over

dbSNP: rs56032526; hg19: chr1-216011361; COSMIC: COSV56343459; API