1-215648629-G-A

Position:

chr1-215648629-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_206933.4(USH2A):c.14481C>T(p.Ala4827Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,160 control chromosomes in the GnomAD database, including 517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 100 hom., cov: 33)

Exomes 𝑓: 0.011 ( 417 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.310

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 1-215648629-G-A is Benign according to our data. Variant chr1-215648629-G-A is described in ClinVar as [Benign]. Clinvar id is 48438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215648629-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.14481C>T	p.Ala4827Ala	synonymous_variant	66/72	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.14481C>T	p.Ala4827Ala	synonymous_variant	66/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.14481C>T	p.Ala4827Ala	synonymous_variant	66/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3539

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0619

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0299

Gnomad SAS

AF:

0.0699

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0168

AC:

4218

AN:

251396

Hom.:

128

AF XY:

0.0183

AC XY:

2489

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0644

Gnomad AMR exome

AF:

0.00396

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0188

Gnomad SAS exome

AF:

0.0693

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00388

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.0109

AC:

15977

AN:

1461854

Hom.:

417

Cov.:

AF XY:

0.0122

AC XY:

8897

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0658

Gnomad4 AMR exome

AF:

0.00467

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0506

Gnomad4 SAS exome

AF:

0.0665

Gnomad4 FIN exome

AF:

0.00253

Gnomad4 NFE exome

AF:

0.00435

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0233

AC:

3552

AN:

152306

Hom.:

100

Cov.:

AF XY:

0.0238

AC XY:

1773

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0620

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0300

Gnomad4 SAS

AF:

0.0702

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0235

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	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	Eurofins Ntd Llc (ga)	May 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2010	Ala4827Ala in exon 66 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and it is not located near a splice junction. In addition, this variant has been identified in 4/191 (2.1%) of individual?s tested by our laboratory with at least 3/4 of Black or Hi spanic background. Therefore, this variant is likley to be a common benign varia nt in these populations. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A

Benign:2

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

Retinitis pigmentosa 39

Benign:1

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

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.58

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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