rs41303285

chr1-215741409-G-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.11677C>A(p.Pro3893Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0194 in 1,613,844 control chromosomes in the GnomAD database, including 396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.020 (377 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 6.11

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009347379).
• BP6: Variant 1-215741409-G-T is Benign according to our data. Variant chr1-215741409-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 48380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215741409-G-T is described in Lovd as [Benign]. Variant chr1-215741409-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1952/152098) while in subpopulation NFE AF= 0.0195 (1325/67990). AF 95% confidence interval is 0.0186. There are 19 homozygotes in gnomad4. There are 983 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• 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.11677C>A	p.Pro3893Thr	missense_variant	60/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.11677C>A	p.Pro3893Thr	missense_variant	60/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.11677C>A	p.Pro3893Thr	missense_variant	60/73

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1954 AN: 151982 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.00960

GnomAD3 exomes AF: 0.0158 AC: 3977 AN: 251428 Hom.: 54 AF XY: 0.0163 AC XY: 2212 AN XY: 135884

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0201 AC: 29380 AN: 1461746 Hom.: 377 Cov.: 31 AF XY: 0.0197 AC XY: 14347 AN XY: 727168

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152098 Hom.: 19 Cov.: 32 AF XY: 0.0132 AC XY: 983 AN XY: 74336

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.00950

Alfa AF: 0.0174 Hom.: 49

Bravo AF: 0.0108

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0224 AC: 193

ExAC AF: 0.0173 AC: 2102

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0153

EpiControl AF: 0.0161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	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. -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy Benign:1

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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.075	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.25
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.38
gMVP		0.63

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: rs41303285; hg19: chr1-215914751; COSMIC: COSV99048391;