rs55961436

chr1-215728168-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_206933.4(USH2A):c.11928G>A(p.Thr3976=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,106 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T3976T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0096 (19 hom., cov: 32)
  • Exomes 𝑓: 0.011 (128 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.43

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-215728168-C-T is Benign according to our data. Variant chr1-215728168-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48386.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=1}. Variant chr1-215728168-C-T is described in Lovd as [Benign]. Variant chr1-215728168-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.11928G>A	p.Thr3976=	synonymous_variant	61/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.11928G>A	p.Thr3976=	synonymous_variant	61/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.11928G>A	p.Thr3976=	synonymous_variant	61/73

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1468 AN: 152108 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00952 AC: 2392 AN: 251312 Hom.: 31 AF XY: 0.00998 AC XY: 1356 AN XY: 135820

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.00500

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.00972

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0109 AC: 15885 AN: 1461880 Hom.: 128 Cov.: 33 AF XY: 0.0108 AC XY: 7882 AN XY: 727242

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.000982

Gnomad4 SAS exome AF: 0.00544

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00907

GnomAD4 genome AF: 0.00964 AC: 1467 AN: 152226 Hom.: 19 Cov.: 32 AF XY: 0.0110 AC XY: 822 AN XY: 74412

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0429

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00818 Hom.: 7

Bravo AF: 0.00624

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00818

EpiControl AF: 0.00812

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2015	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	Jul 02, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 2A Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	literature only	Molecular Genetics Laboratory; Baylor College of Medicine	-	- -

Retinal dystrophy Benign:1

Likely 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	-0.71
Cadd	Benign	1.6
Dann	Benign	0.36

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: rs55961436; hg19: chr1-215901510;