rs1553313909

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The ENST00000307340.8(USH2A):​c.3317-1G>A variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

USH2A
ENST00000307340.8 splice_acceptor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.48
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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03164841 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 1, new splice context is: ttttttcttttcatttcaAGtat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-216200122-C-T is Pathogenic according to our data. Variant chr1-216200122-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553748.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-216200122-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.3317-1G>A splice_acceptor_variant ENST00000307340.8 NP_996816.3
USH2A-AS1XR_922596.4 linkuse as main transcriptn.691+4197C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.3317-1G>A splice_acceptor_variant 1 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.3317-1G>A splice_acceptor_variant 1 ENSP00000355909 O75445-2
USH2A-AS1ENST00000420867.1 linkuse as main transcriptn.363-3908C>T intron_variant, non_coding_transcript_variant 3
USH2AENST00000674083.1 linkuse as main transcriptc.3317-1G>A splice_acceptor_variant ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1451104
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
721492
Gnomad4 AFR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylSep 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
28
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
6.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.32
Position offset: -2
DS_AL_spliceai
0.95
Position offset: -1

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: rs1553313909; hg19: chr1-216373464; API