rs397517989

Positions:

• chr1-215650755-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.14180G>A​(p.Trp4727Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.776

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 1-215650755-C-T is Pathogenic according to our data. Variant chr1-215650755-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215650755-C-T is described in Lovd as [Pathogenic]. Variant chr1-215650755-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.14180G>A	p.Trp4727Ter	stop_gained	65/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14180G>A	p.Trp4727Ter	stop_gained	65/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14180G>A	p.Trp4727Ter	stop_gained	65/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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	Mar 18, 2024	- -
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

May 11, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48429). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 25649381, 29912909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp4727*) 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). -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2012

The Trp4727X variant in USH2A has not been reported in the literature nor previo usly identified by our laboratory. This nonsense variant leads to a premature te rmination codon at position 4727, which is predicted to lead to a truncated or a bsent protein. In summary, this variant meets our criteria to be classified as p athogenic (http://pcpgm.partners.org/LMM). -

Usher syndrome type 2A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.36	N
MutationTaster	Benign	1.0	A;A
Vest4		0.77
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs397517989; hg19: chr1-215824097;