1-216175474-G-A

Position:

• chr1-216175474-G-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.4405C>T​(p.Gln1469Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH2A NM_206933.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.76

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 1-216175474-G-A is Pathogenic according to our data. Variant chr1-216175474-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216175474-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4405C>T	p.Gln1469Ter	stop_gained	21/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4405C>T	p.Gln1469Ter	stop_gained	21/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4405C>T	p.Gln1469Ter	stop_gained	21/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.4405C>T	p.Gln1469Ter	stop_gained	21/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.4405C>T	p.Gln1469Ter	stop_gained	21/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461474 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727030

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 21, 2014	The p.Gln1469X variant in USH2A has been reported in 1 compound heterozygous individual with Usher syndrome type II (Pennings 2004) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1469, which is predicted to lead to a truncated or absent protein. Complete loss-of-function of the USH2A gene is an established disease mechanism in individuals with Usher syndrome type II. In summary, the p.Gln1469X variant in USH2A meets our criteria to be classified as pathogenic for Usher syndrome type II in an autosomal recessive manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2020

This sequence change creates a premature translational stop signal (p.Gln1469*) 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). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Usher syndrome (PMID: 15241801, 27318125). This variant is also known as p.Gln1468X in the literature. ClinVar contains an entry for this variant (Variation ID: 208625). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.77
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs797045113; hg19: chr1-216348816;