rs117798425

Positions:

• chr1-216097080-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):​c.4758+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000568 in 1,613,506 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (10 hom.)
• Consequence: USH2A NM_206933.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9624
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 4.49

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 Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 1-216097080-T-C is Benign according to our data. Variant chr1-216097080-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 156396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216097080-T-C is described in Lovd as [Benign]. Variant chr1-216097080-T-C is described in Lovd as [Likely_benign]. Variant chr1-216097080-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000761 (116/152358) while in subpopulation EAS AF= 0.0183 (95/5190). AF 95% confidence interval is 0.0153. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.4758+3A>G		splice_donor_region_variant, intron_variant		ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.4758+3A>G		splice_donor_region_variant, intron_variant		1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.4758+3A>G		splice_donor_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00151 AC: 378 AN: 249948 Hom.: 5 AF XY: 0.00142 AC XY: 192 AN XY: 135234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0181

Gnomad SAS exome AF: 0.000786

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1461148 Hom.: 10 Cov.: 31 AF XY: 0.000583 AC XY: 424 AN XY: 726850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000761 AC: 116 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0183

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2018	This variant is associated with the following publications: (PMID: 25445212, 25404053, 30245029, 29625443, 31180159, 31904091, 32090030, 32893482, 33090715) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 22, 2017	c.4758+3A>G in intron 22 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.9% (348/18756) of East Asian c hromosomes, including 4 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs117798425). ACMG/AMP Criteria applie d: BA1. -

Leber congenital amaurosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Diagnostics Laboratory, Seoul National University Hospital

Sep 18, 2014

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 10, 2022

- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs117798425; hg19: chr1-216270422;