rs11120645

Positions:

• chr1-215817137-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.9430G>A​(p.Asp3144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,664 control chromosomes in the GnomAD database, including 773 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (96 hom., cov: 32)
  • Exomes 𝑓: 0.028 (677 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.34

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 0 benign, 7 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061059594).
• BP6: Variant 1-215817137-C-T is Benign according to our data. Variant chr1-215817137-C-T is described in ClinVar as [Benign]. Clinvar id is 48627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215817137-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9430G>A	p.Asp3144Asn	missense_variant	48/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9430G>A	p.Asp3144Asn	missense_variant	48/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9430G>A	p.Asp3144Asn	missense_variant	48/73

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5133 AN: 151854 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0446

GnomAD3 exomes AF: 0.0260 AC: 6499 AN: 250212 Hom.: 86 AF XY: 0.0257 AC XY: 3469 AN XY: 135178

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00448

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0284 AC: 41486 AN: 1460694 Hom.: 677 Cov.: 30 AF XY: 0.0279 AC XY: 20263 AN XY: 726656

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0398

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00348

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0303

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0339 AC: 5146 AN: 151970 Hom.: 96 Cov.: 32 AF XY: 0.0336 AC XY: 2494 AN XY: 74256

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.0359

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0446

Alfa AF: 0.0301 Hom.: 128

Bravo AF: 0.0376

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.0522 AC: 230

ESP6500EA AF: 0.0301 AC: 259

ExAC AF: 0.0265 AC: 3212

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0297

EpiControl AF: 0.0352

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -
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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.59	D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		0.022	B
Vest4		0.054
MPC		0.033
ClinPred		0.017	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.35

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: rs11120645; hg19: chr1-215990479; COSMIC: COSV56389684;