1-215741541-GAA-GA

Position:

• chr1-215741541-GAA-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.11549-5del 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 0.0163 in 1,117,120 control chromosomes in the GnomAD database, including 134 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.017 (114 hom.)
• Consequence: USH2A NM_206933.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.396

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 -16 ACMG points.

• BP6: Variant 1-215741541-GA-G is Benign according to our data. Variant chr1-215741541-GA-G is described in ClinVar as [Benign]. Clinvar id is 177774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215741541-GA-G is described in Lovd as [Benign]. Variant chr1-215741541-GA-G is described in Lovd as [Benign]. Variant chr1-215741541-GA-G is described in Lovd as [Likely_pathogenic].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.11549-5del		splice_region_variant, splice_polypyrimidine_tract_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.11549-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.11549-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1405 AN: 138720 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.000775

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0520 AC: 6144 AN: 118084 Hom.: 63 AF XY: 0.0486 AC XY: 3069 AN XY: 63212

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0674

Gnomad SAS exome AF: 0.0792

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0171 AC: 16767 AN: 978338 Hom.: 114 Cov.: 33 AF XY: 0.0176 AC XY: 8548 AN XY: 485518

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0388

Gnomad4 SAS exome AF: 0.0464

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00966

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0102 AC: 1414 AN: 138782 Hom.: 20 Cov.: 32 AF XY: 0.0110 AC XY: 737 AN XY: 66892

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0416

Gnomad4 ASJ AF: 0.000304

Gnomad4 EAS AF: 0.0236

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.000775

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.0195

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2014	11549-5delT in intron 59 of USH2A: This variant is not expected to have clinica l significance because it has been identified in 2.0% (166/8241) of European Am erican chromosomes by the NHLBI Exome Sequencing Project, it occurs within a pol y-T tract, and is not predicted to impact splicing (http://evs.gs.washington.edu /EVS/; dbSNP rs34565443). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2019	This variant is associated with the following publications: (PMID: 31054281) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs34565443; hg19: chr1-215914883;