rs41304083

chr1-215648629-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):c.14481C>T(p.Ala4827=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.310

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 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	UniProt
USH2A	NM_206933.4	c.14481C>T	p.Ala4827=	synonymous_variant	66/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14481C>T	p.Ala4827=	synonymous_variant	66/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14481C>T	p.Ala4827=	synonymous_variant	66/73

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3539 AN: 152188 Hom.: 97 Cov.: 33

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

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.: 31 AF XY: 0.0122 AC XY: 8897 AN XY: 727224

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.: 33 AF XY: 0.0238 AC XY: 1773 AN XY: 74458

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.: 21

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 2A Benign:2

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

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

Other links and lift over

dbSNP: rs41304083; hg19: chr1-215821971;