chr1-215782762-A-T

Position:

• chr1-215782762-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Moderate

The NM_206933.4(USH2A):​c.10561T>A​(p.Trp3521Arg) variant causes a missense change involving the alteration of a 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.07

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.

• PS1: Transcript NM_206933.4 (USH2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 48352
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-215782762-A-T is Pathogenic according to our data. Variant chr1-215782762-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1376832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.10561T>A	p.Trp3521Arg	missense_variant	53/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.10561T>A	p.Trp3521Arg	missense_variant	53/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.10561T>A	p.Trp3521Arg	missense_variant	53/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Usher syndrome (PMID: 22135276, 28559085). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 3521 of the USH2A protein (p.Trp3521Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.78		Loss of catalytic residue at L3519 (P = 0.0203);
MVP		0.91
MPC		0.29
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-215956104;