chr1-216323605-G-A

Position:

• chr1-216323605-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000307340.8(USH2A):​c.1419C>T​(p.Thr473=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,018 control chromosomes in the GnomAD database, including 51,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T473T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6189 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45341 hom.)
• Consequence: USH2A ENST00000307340.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.582

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-216323605-G-A is Benign according to our data. Variant chr1-216323605-G-A is described in ClinVar as [Benign]. Clinvar id is 48431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216323605-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.582 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1419C>T	p.Thr473=	synonymous_variant	8/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1419C>T	p.Thr473=	synonymous_variant	8/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1419C>T	p.Thr473=	synonymous_variant	8/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.1419C>T	p.Thr473=	synonymous_variant	8/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.1419C>T	p.Thr473=	synonymous_variant	8/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42091 AN: 151598 Hom.: 6167 Cov.: 31

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.287

GnomAD3 exomes AF: 0.250 AC: 62657 AN: 250742 Hom.: 8151 AF XY: 0.250 AC XY: 33833 AN XY: 135486

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.280

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.246 AC: 359394 AN: 1461302 Hom.: 45341 Cov.: 34 AF XY: 0.247 AC XY: 179765 AN XY: 726942

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.278 AC: 42142 AN: 151716 Hom.: 6189 Cov.: 31 AF XY: 0.274 AC XY: 20276 AN XY: 74092

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.285

Alfa AF: 0.260 Hom.: 10719

Bravo AF: 0.289

Asia WGS AF: 0.203 AC: 707 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -

Usher syndrome type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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:2

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

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.9
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1805050; hg19: chr1-216496947; COSMIC: COSV56343492;