rs56032526

chr1-215838019-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):c.9343A>G(p.Thr3115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 1,613,802 control chromosomes in the GnomAD database, including 2,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (168 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2363 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0680

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.001318723).
• BP6: Variant 1-215838019-T-C is Benign according to our data. Variant chr1-215838019-T-C is described in ClinVar as [Benign]. Clinvar id is 48623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838019-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9343A>G	p.Thr3115Ala	missense_variant	47/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9343A>G	p.Thr3115Ala	missense_variant	47/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9343A>G	p.Thr3115Ala	missense_variant	47/73

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5492 AN: 152178 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0769

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0439

GnomAD3 exomes AF: 0.0497 AC: 12498 AN: 251308 Hom.: 550 AF XY: 0.0504 AC XY: 6839 AN XY: 135814

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0580

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.0814

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0490 AC: 71657 AN: 1461506 Hom.: 2363 Cov.: 31 AF XY: 0.0496 AC XY: 36036 AN XY: 727078

Gnomad4 AFR exome AF: 0.00812

Gnomad4 AMR exome AF: 0.0579

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.0805

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.0464

Gnomad4 OTH exome AF: 0.0553

GnomAD4 genome AF: 0.0360 AC: 5486 AN: 152296 Hom.: 168 Cov.: 32 AF XY: 0.0364 AC XY: 2714 AN XY: 74468

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0538

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.0768

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0421

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0423 Hom.: 294

Bravo AF: 0.0371

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0398 AC: 342

ExAC AF: 0.0487 AC: 5917

Asia WGS AF: 0.112 AC: 387 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -

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	Jul 01, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	0.065
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.7
Dann	Benign	0.44
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.14
Sift	Benign	0.79	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.030
ClinPred		0.0032	T
GERP RS		-5.6
Varity_R		0.034
gMVP		0.20

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

Other links and lift over

dbSNP: rs56032526; hg19: chr1-216011361; COSMIC: COSV56343459;