rs75397806

Positions:

• chr1-215782771-C-T

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.10552G>A​(p.Val3518Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,870 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (15 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0710

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 2 benign, 4 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.005207777).
• BP6: Variant 1-215782771-C-T is Benign according to our data. Variant chr1-215782771-C-T is described in ClinVar as [Benign]. Clinvar id is 48351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215782771-C-T is described in Lovd as [Likely_benign]. Variant chr1-215782771-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00636 (968/152254) while in subpopulation AFR AF= 0.0218 (907/41558). AF 95% confidence interval is 0.0206. There are 8 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.10552G>A	p.Val3518Ile	missense_variant	53/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.10552G>A	p.Val3518Ile	missense_variant	53/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.10552G>A	p.Val3518Ile	missense_variant	53/73

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 963 AN: 152136 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00159 AC: 400 AN: 251158 Hom.: 8 AF XY: 0.00117 AC XY: 159 AN XY: 135742

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000607 AC: 887 AN: 1461616 Hom.: 15 Cov.: 31 AF XY: 0.000507 AC XY: 369 AN XY: 727114

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00636 AC: 968 AN: 152254 Hom.: 8 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74448

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00116 Hom.: 6

Bravo AF: 0.00740

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2011	Val3518Ile in exon 53 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in over 1% of controls (rs75397806). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 28838317) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 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	0.067
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.2
DANN	Benign	0.90
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.094
Sift	Benign	0.51	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.097
MVP		0.21
MPC		0.027
ClinPred		0.0046	T
GERP RS		0.95
Varity_R		0.024
gMVP		0.28

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: rs75397806; hg19: chr1-215956113; COSMIC: COSV56400171;