rs1553252404

Positions:

• chr1-215674673-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_206933.4(USH2A):​c.13238C>G​(p.Pro4413Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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 8 ACMG points.

• PM1: In a domain Fibronectin type-III 29 (size 87) in uniprot entity USH2A_HUMAN there are 40 pathogenic changes around while only 4 benign (91%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.13238C>G	p.Pro4413Arg	missense_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.13238C>G	p.Pro4413Arg	missense_variant	63/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.13238C>G	p.Pro4413Arg	missense_variant	63/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 27, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro4413Ar g variant in USH2A has been reported by our laboratory in one individual with he aring loss, who has another variant of uncertain significance on the same copy a nd a pathogenic variant on the other copy of the USH2A gene. The p.Pro4413Arg ha s not been identified in large population studies. Computational prediction tool s and conservation analyses suggest that this variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, while there is some suspicion of a pathogenic role, the clinical signific ance of the p.Pro4413Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.097	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.66
Sift	Benign	0.070	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.85		Gain of catalytic residue at P4413 (P = 0.1969);
MVP		0.96
MPC		0.24
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.60

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: rs1553252404; hg19: chr1-215848015;