rs199605265

Positions:

• chr1-215675336-C-A
• chr1-215675336-C-G
• chr1-215675336-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_206933.4(USH2A):​c.12575G>T​(p.Arg4192Leu) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4192C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215675337-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281818.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.12575G>T	p.Arg4192Leu	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.12575G>T	p.Arg4192Leu	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.12575G>T	p.Arg4192Leu	missense_variant	63/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg4192 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29912909, 27157150, 23940504). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 4192 of the USH2A protein (p.Arg4192Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.68	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.030	D
Sift4G	Benign	0.067	T
Polyphen		0.82	P
Vest4		0.42
MutPred		0.67		Loss of MoRF binding (P = 0.0276);
MVP		0.97
MPC		0.24
ClinPred		0.88	D
GERP RS		4.2
Varity_R		0.31
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-215848678; COSMIC: COSV56383021;