rs147900972

chr1-215743321-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):c.11404G>A(p.Glu3802Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,596,618 control chromosomes in the GnomAD database, including 8 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 26)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.694

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034196079).
• BP6: Variant 1-215743321-C-T is Benign according to our data. Variant chr1-215743321-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215743321-C-T is described in Lovd as [Likely_benign]. Variant chr1-215743321-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.11404G>A	p.Glu3802Lys	missense_variant	59/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.11404G>A	p.Glu3802Lys	missense_variant	59/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.11404G>A	p.Glu3802Lys	missense_variant	59/73

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 234 AN: 144234 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00836

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00103

GnomAD3 exomes AF: 0.00249 AC: 621 AN: 249888 Hom.: 3 AF XY: 0.00246 AC XY: 333 AN XY: 135138

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00177 AC: 2567 AN: 1452288 Hom.: 7 Cov.: 32 AF XY: 0.00182 AC XY: 1318 AN XY: 722656

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.000384

Gnomad4 ASJ exome AF: 0.000232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00162 AC: 234 AN: 144330 Hom.: 1 Cov.: 26 AF XY: 0.00189 AC XY: 132 AN XY: 69886

Gnomad4 AFR AF: 0.000256

Gnomad4 AMR AF: 0.00129

Gnomad4 ASJ AF: 0.000292

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00836

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00102

Alfa AF: 0.00209 Hom.: 1

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00252 AC: 306

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2022	Variant summary: USH2A c.11404G>A (p.Glu3802Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 249888 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0025 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no penetrant association of c.11404G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2017	p.Glu3802Lys in exon 59 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.3% (280/21974) of Finnish chrom osomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs147900972). In addition, computational anal yses do not suggest a high likelihood of clinical significance primarily based u pon a lack of conservation across species including mammals. Of note, orangutan, rat, mouse, dog and cow have a lysine at this position despite high nearby amin o acid conservation. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

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	GeneDx	Sep 03, 2019	This variant is associated with the following publications: (PMID: 32707200) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A Benign:1

Likely 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	0.063
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.13
Dann	Benign	0.31
DEOGEN2	Benign	0.026	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
MVP		0.67
MPC		0.032
ClinPred		0.0036	T
GERP RS		-9.9
Varity_R		0.052
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs147900972; hg19: chr1-215916663; COSMIC: COSV104600402;