1-215780013-G-A

Position:

chr1-215780013-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_206933.4(USH2A):c.10769C>T(p.Pro3590Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000781 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3590P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 4.82

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14373487).

BP6

Variant 1-215780013-G-A is Benign according to our data. Variant chr1-215780013-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48358.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=1}. Variant chr1-215780013-G-A is described in Lovd as [Likely_benign]. Variant chr1-215780013-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.10769C>T	p.Pro3590Leu	missense_variant	55/72	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.10769C>T	p.Pro3590Leu	missense_variant	55/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.10769C>T	p.Pro3590Leu	missense_variant	55/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000621

AC:

156

AN:

251166

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000804

AC:

1175

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000771

AC XY:

561

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000565

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000911

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000758

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 2A

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 30, 2019	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2010	Pro3590Leu in exon 55 of USH2A: This variant is not expected to have clinical si gnificance because Pro3590 is not conserved among closely related species with R at having a Leucine (Leu) at this position. In addition, this variant was found occur at an equal frequency between probands and a control population (Dreyer 20 08). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.5

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.61

Sift

Benign

0.049

Sift4G

Pathogenic

0.0

Polyphen

0.45

Vest4

0.58

MVP

0.97

MPC

0.13

ClinPred

0.31

GERP RS

4.9

Varity_R

0.19

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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