rs77792891

Positions:

• chr1-215625868-A-G

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.15522T>C​(p.Tyr5174=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,613,968 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (448 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (396 hom.)
• Consequence: USH2A NM_206933.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0440

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=-0.66).
• BP6: Variant 1-215625868-A-G is Benign according to our data. Variant chr1-215625868-A-G is described in ClinVar as [Benign]. Clinvar id is 48467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215625868-A-G is described in Lovd as [Benign]. Variant chr1-215625868-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.044 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.15522T>C	p.Tyr5174=	splice_region_variant, synonymous_variant	72/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.15522T>C	p.Tyr5174=	splice_region_variant, synonymous_variant	72/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000674083.1	c.15594T>C	p.Tyr5198=	splice_region_variant, synonymous_variant	73/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6311 AN: 152150 Hom.: 449 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0119 AC: 2981 AN: 251312 Hom.: 185 AF XY: 0.00885 AC XY: 1202 AN XY: 135844

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00485 AC: 7084 AN: 1461702 Hom.: 396 Cov.: 30 AF XY: 0.00424 AC XY: 3084 AN XY: 727168

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.00870

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0415 AC: 6317 AN: 152266 Hom.: 448 Cov.: 32 AF XY: 0.0407 AC XY: 3030 AN XY: 74474

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0208 Hom.: 89

Bravo AF: 0.0480

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2011	Tyr5174Tyr in exon 72 of USH2A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located near a splice junction, and has been identified in 19.5% (23/118) of African control chromosomes and 5.2% (301/5823) of general population control chromosomes. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 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. -

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	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2022

- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.090
DANN	Benign	0.77

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: rs77792891; hg19: chr1-215799210;