rs727503714

chr1-215634475-G-Achr1-215634475-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_206933.4(USH2A):c.15281C>T(p.Pro5094Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P5094P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.67

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27106875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.15281C>T	p.Pro5094Leu	missense_variant	70/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.15281C>T	p.Pro5094Leu	missense_variant	70/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.15281C>T	p.Pro5094Leu	missense_variant	70/73

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251414 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135882

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 09, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2022	Reported without a second variant in a patient with family history of hearing loss in published literature (Almontashiri et al., 2018); additional information is limited; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29048421) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5094 of the USH2A protein (p.Pro5094Leu). This variant is present in population databases (rs727503714, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 166415). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function. 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. -

Usher syndrome type 2A Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Pro5094Leu vari ant in USH2A has not been previously reported in individuals with hearing loss a nd was absent from large population studies. The proline (Pro) at position 5094 is not conserved in mammals or evolutionary distant species, suggesting that var iation at this position may be tolerated. Other computational prediction tools d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of this variant cannot be determined with certainty; however, based upon conservation data, we would lean towards a more likely beni gn role. -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.089
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.069
Sift	Benign	0.066	T
Sift4G	Uncertain	0.022	D
Polyphen		0.91	P
Vest4		0.34
MutPred		0.28		Loss of catalytic residue at P5093 (P = 0.0281);
MVP		0.82
MPC		0.046
ClinPred		0.38	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs727503714; hg19: chr1-215807817;