rs748810737

Positions:

• chr1-215844293-C-A
• chr1-215844293-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000307340.8(USH2A):​c.9258+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.000000684 in 1,461,120 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A ENST00000307340.8 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.4, offset of 22, new splice context is: atgGTtagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-215844293-C-A is Pathogenic according to our data. Variant chr1-215844293-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215844293-C-A is described in Lovd as [Pathogenic]. Variant chr1-215844293-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.9258+1G>T		splice_donor_variant		ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.9258+1G>T		splice_donor_variant		1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.9258+1G>T		splice_donor_variant				ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461120 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 02, 2023	- -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 12, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 26, 2023

Variant summary: USH2A c.9258+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, to our knowledge these predictions have yet to be confirmed by functional studies. The variant was absent in 250118 control chromosomes (gnomAD). c.9258+1G>T has been reported in the literature in individuals affected with retinitis pigmentosa (example: Koyanagi_2019, Martin-Merida_2019, Kim_2021, and Ma_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31213501, 30902645, 33946315, 33691693). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 14, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 555604). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 30902645, 31047384). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 46 of the USH2A 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 USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). -

Usher syndrome type 2A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs748810737; hg19: chr1-216017635; COSMIC: COSV56388217;