rs111033381

chr1-215674614-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):c.13297G>T(p.Val4433Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,614,142 control chromosomes in the GnomAD database, including 472 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V4433V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.27

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023987293).
• BP6: Variant 1-215674614-C-A is Benign according to our data. Variant chr1-215674614-C-A is described in ClinVar as [Benign]. Clinvar id is 48415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215674614-C-A is described in Lovd as [Benign]. Variant chr1-215674614-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0182 (2775/152280) while in subpopulation NFE AF= 0.0244 (1660/68022). AF 95% confidence interval is 0.0234. There are 46 homozygotes in gnomad4. There are 1397 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.13297G>T	p.Val4433Leu	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.13297G>T	p.Val4433Leu	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.13297G>T	p.Val4433Leu	missense_variant	63/73

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2775 AN: 152162 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0191 AC: 4802 AN: 250872 Hom.: 69 AF XY: 0.0188 AC XY: 2543 AN XY: 135548

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0219 AC: 32020 AN: 1461862 Hom.: 426 Cov.: 31 AF XY: 0.0212 AC XY: 15446 AN XY: 727226

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.0481

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0182 AC: 2775 AN: 152280 Hom.: 46 Cov.: 32 AF XY: 0.0188 AC XY: 1397 AN XY: 74460

Gnomad4 AFR AF: 0.00346

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0231 Hom.: 61

Bravo AF: 0.0157

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0192 AC: 2330

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0220

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

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	Jun 17, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2014	- -

not provided Benign:2 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	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Usher syndrome type 2A Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -
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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.3
Dann	Benign	0.91
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.055
Sift	Benign	0.32	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.39		Loss of catalytic residue at V4433 (P = 0.1009);
MPC		0.030
ClinPred		0.016	T
GERP RS		-0.13
Varity_R		0.040
gMVP		0.22

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: rs111033381; hg19: chr1-215847956; COSMIC: COSV56394744;