rs201558076

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The ENST00000307340.8(USH2A):​c.3158-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,844 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

USH2A
ENST00000307340.8 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.0004707
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.108
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 1-216207438-T-C is Benign according to our data. Variant chr1-216207438-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228212.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.3158-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000307340.8 NP_996816.3
USH2A-AS1XR_922596.4 linkuse as main transcriptn.691+11513T>C intron_variant, non_coding_transcript_variant
USH2ANM_007123.6 linkuse as main transcriptc.3158-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant NP_009054.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.3158-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.3158-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 ENSP00000355909 O75445-2
USH2AENST00000674083.1 linkuse as main transcriptc.3158-7A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.000881
AC:
134
AN:
152092
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00304
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.000957
GnomAD3 exomes
AF:
0.000191
AC:
48
AN:
250944
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135622
show subpopulations
Gnomad AFR exome
AF:
0.00271
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000814
AC:
119
AN:
1461634
Hom.:
1
Cov.:
31
AF XY:
0.0000646
AC XY:
47
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.00269
Gnomad4 AMR exome
AF:
0.000179
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:
0.00000270
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000900
AC:
137
AN:
152210
Hom.:
1
Cov.:
32
AF XY:
0.000995
AC XY:
74
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.00311
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000691
Hom.:
0
Bravo
AF:
0.000971
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 26, 2015c.3158-7A>G in intron 15 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.3% (28/10558) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201558076). -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 15, 2024Variant summary: USH2A c.3158-7A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00016 in 1613844 control chromosomes, predominantly at a frequency of 0.0029 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00016 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3158-7A>G in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 228212). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxAug 31, 2020- -
Retinitis pigmentosa 39 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Usher syndrome type 2A Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
9.5
DANN
Benign
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00047
dbscSNV1_RF
Benign
0.076
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: rs201558076; hg19: chr1-216380780; API