chr1-215816996-C-T

Position:

• chr1-215816996-C-T

Variant summary

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

The NM_206933.4(USH2A):​c.9570+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000685 in 1,460,018 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: USH2A NM_206933.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 5.75

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, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-215816996-C-T is Pathogenic according to our data. Variant chr1-215816996-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 228418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215816996-C-T is described in Lovd as [Pathogenic]. Variant chr1-215816996-C-T is described in Lovd as [Pathogenic]. Variant chr1-215816996-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.9570+1G>A		splice_donor_variant, intron_variant		ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.9570+1G>A		splice_donor_variant, intron_variant		1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.9570+1G>A		splice_donor_variant, intron_variant				ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250384 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460018 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

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

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 03, 2024	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.9570+1G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3, PP1-M. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Pangenia Genomics, Pangenia Inc.	Nov 18, 2021	The USH2A, c.9570+1G>A variant is at a canonical ±1 or 2 splice site, resulting in a null variant. This variant is at extremely low frequency in population database; allele frequency in East Asia population is 0.0005 by gnomAD v2.1.1. This variant is detected in trans with a pathogenic variant [USH2A, c.2802T>G (p.Cys934Trp)]. This variant has been previously reported to be detected in a deaf patient (Usher syndrome), in trans with c.1992_1993insT [PMID: 23767834] and in another two Usher syndrome patients who are from the same family, in trans with c.8559-2A>G [PMID: 25252889]. There is co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. This variant has been reported to co-segregate with Usher syndrome or RP in at least 4 families [PMID: 23737954, 24938718, 25252889, 3094874]. There are multiple submissions of this variant in ClinVar (Variation ID: 228418), all rated as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Usher syndrome type 2A Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000228418). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). The variant has been reported to be in trans with a pathogenic variant (NM_206933.4:c.2187C>A) as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24938718, 23767834, 23737954, 25252889, 30948794, 33111992, 32188678, 34130719, 32675063) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2023	This sequence change affects a donor splice site in intron 48 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). This variant is present in population databases (rs760225886, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with Usher syndrome and USH2A-related diseases (PMID: 23737954, 23767834, 24938718). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS48+1G>A. ClinVar contains an entry for this variant (Variation ID: 228418). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 20, 2018	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2015

The c.9570+1G>A variant in USH2A has been reported in 4 Chinese individuals: 2 w ith Usher syndrome, 1 with hearing loss, and 1 with retinitis pigmentosa, and se gregated with disease in at least 3 affected individuals from 3 families (Huang 2013, Yang 2013, Xu 2014, Qu 2014). All of these individuals were compound hete rozygous. In addition, this variant has been identified in 7/8606 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. The c.9 570+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensu s sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome (www.partners.org/personalized medicine/lmm). -

USH2A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2023

The USH2A c.9570+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in as causative in patients with autosomal recessive Usher syndrome, retinitis pigmentosa or nonsyndromic hearing loss (Qu. 2014. PubMed ID: 25252889; Yang. 2013. PubMed ID: 23767834; Xu. 2014. PubMed ID: 24938718). This variant is reported in 0.054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215990338-C-T). Variants that disrupt the consensus splice donor site in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
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: rs760225886; hg19: chr1-215990338;