rs727503715

Positions:

• chr1-215674536-AT-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.13374delA​(p.Glu4458fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.193

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: 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 1-215674536-AT-A is Pathogenic according to our data. Variant chr1-215674536-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 166428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215674536-AT-A is described in Lovd as [Pathogenic]. Variant chr1-215674536-AT-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.13374delA	p.Glu4458fs	frameshift_variant	63/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13374delA	p.Glu4458fs	frameshift_variant	63/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.13374delA	p.Glu4458fs	frameshift_variant	63/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250388 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135294

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727234

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: 0.0000531

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2017	The c.13374delA variant in the USH2 gene has been reported previously in the compound heterozygous state with a second USH2 variant in patients with Usher syndrome type II (Baux et al., 2007; Le Quesne Stabej et al., 2012). The c.13374delA variant causes a frameshift starting with codon Glutamic Acid 4458, changes this amino acid to a Aspartic Acid residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Glu4458AspfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.13374delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.13374delA as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 11, 2023	This sequence change creates a premature translational stop signal (p.Glu4458Aspfs*3) 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 (rs727503715, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with USH2A-related conditions (PMID: 17405132, 28041643). ClinVar contains an entry for this variant (Variation ID: 166428). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 02, 2024	- -

Usher syndrome type 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 09, 2024	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2014

The p.Glu4458fs variant in USH2A has been reported in four individuals with Ushe r syndrome, all of whom are compound heterozygous with a second pathogenic USH2A variant (Baux 2007, Stabej 2012). It has not been identified in large populat ion studies. This variant is predicted to cause a frameshift, which alters the p rotein?s amino acid sequence beginning at position 4458 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. In summary, this variant meets our crit eria to be classified as pathogenic for usher syndrome in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm). -

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: rs727503715; hg19: chr1-215847878;