rs41303285

Positions:

chr1-215741409-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.11677C>A(p.Pro3893Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0194 in 1,613,844 control chromosomes in the GnomAD database, including 396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.020 ( 377 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 6.11

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 -18 ACMG points.

PM1

In a domain Fibronectin type-III 24 (size 97) in uniprot entity USH2A_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.009347379).

BP6

Variant 1-215741409-G-T is Benign according to our data. Variant chr1-215741409-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 48380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215741409-G-T is described in Lovd as [Benign]. Variant chr1-215741409-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1952/152098) while in subpopulation NFE AF= 0.0195 (1325/67990). AF 95% confidence interval is 0.0186. There are 19 homozygotes in gnomad4. There are 983 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.11677C>A	p.Pro3893Thr	missense_variant	60/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.11677C>A	p.Pro3893Thr	missense_variant	60/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.11677C>A	p.Pro3893Thr	missense_variant	60/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1954

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.0323

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.00960

GnomAD3 exomes

AF:

0.0158

AC:

3977

AN:

251428

Hom.:

AF XY:

0.0163

AC XY:

2212

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00350

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.0323

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0201

AC:

29380

AN:

1461746

Hom.:

377

Cov.:

AF XY:

0.0197

AC XY:

14347

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.00360

Gnomad4 ASJ exome

AF:

0.00306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.0319

Gnomad4 NFE exome

AF:

0.0225

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0128

AC:

1952

AN:

152098

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

983

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00335

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0125

Gnomad4 FIN

AF:

0.0323

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.0174

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0224

AC:

193

ExAC

AF:

0.0173

AC:

2102

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0153

EpiControl

AF:

0.0161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	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, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2017	- -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

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

0.17

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.60

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.34

Sift

Benign

0.075

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.22

MPC

0.25

ClinPred

0.026

GERP RS

4.4

Varity_R

0.38

gMVP

0.63

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