rs1553274448

chr1-215900175-AC-A

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.7493del(p.Ser2498MetfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.100

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-215900175-AC-A is Pathogenic according to our data. Variant chr1-215900175-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215900175-AC-A is described in Lovd as [Pathogenic]. Variant chr1-215900175-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7493del	p.Ser2498MetfsTer30	frameshift_variant	40/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.7493del	p.Ser2498MetfsTer30	frameshift_variant	40/72	1	NM_206933.4	P1
	ENST00000414995.1	n.61-549del		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7493del	p.Ser2498MetfsTer30	frameshift_variant	40/73

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250694 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460960 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneID Lab - Advanced Molecular Diagnostics	Mar 10, 2018	This variant deletes one nucleotide resulting in an amino acid alteration, replacing a serine (S) with a methionine (M) at codon 2498 creating a premature stop signal in the new reading frame noted as p.S2498Mfs*30. The substitution is predicted to result in a non-functional USH2A protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the Clinical Variant Database (NCBI National Library of Medicine, NIH) or in population databases such as ExAC or 1000G. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Oct 26, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change creates a premature translational stop signal (p.Ser2498Metfs*30) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa or Usher syndrome type II (PMID: 18641288, 20507924). ClinVar contains an entry for this variant (Variation ID: 554589). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1553274448; hg19: chr1-216073517;