rs11120616

Positions:

chr1-215743221-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.11504C>T(p.Thr3835Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,605,504 control chromosomes in the GnomAD database, including 37,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3835T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 2981 hom., cov: 28)

Exomes 𝑓: 0.21 ( 34972 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.36

Variant links:

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002463013).

BP6

Variant 1-215743221-G-A is Benign according to our data. Variant chr1-215743221-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215743221-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11504C>T	p.Thr3835Ile	missense_variant	59/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11504C>T	p.Thr3835Ile	missense_variant	59/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11504C>T	p.Thr3835Ile	missense_variant	59/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28587

AN:

149672

Hom.:

2984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.215

GnomAD3 exomes

AF:

0.191

AC:

48017

AN:

250788

Hom.:

5055

AF XY:

0.191

AC XY:

25844

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.0927

Gnomad SAS exome

AF:

0.0974

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.214

AC:

311628

AN:

1455712

Hom.:

34972

Cov.:

AF XY:

0.211

AC XY:

152604

AN XY:

724170

show subpopulations

Gnomad4 AFR exome

AF:

0.140

Gnomad4 AMR exome

AF:

0.199

Gnomad4 ASJ exome

AF:

0.198

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.0989

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.228

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.191

AC:

28585

AN:

149792

Hom.:

2981

Cov.:

AF XY:

0.188

AC XY:

13706

AN XY:

72990

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.207

Gnomad4 ASJ

AF:

0.196

Gnomad4 EAS

AF:

0.104

Gnomad4 SAS

AF:

0.0768

Gnomad4 FIN

AF:

0.223

Gnomad4 NFE

AF:

0.228

Gnomad4 OTH

AF:

0.212

Alfa

AF:

0.216

Hom.:

8664

Bravo

AF:

0.191

ESP6500AA

AF:

0.143

AC:

628

ESP6500EA

AF:

0.233

AC:

2005

ExAC

AF:

0.192

AC:

23297

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 2A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

Eigen

Benign

-0.11

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

REVEL

Benign

0.10

Sift

Benign

0.18

Sift4G

Benign

0.076

Polyphen

0.055

Vest4

0.031

MPC

0.039

ClinPred

0.012

GERP RS

4.9

Varity_R

0.11

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over