rs144783615

chr1-215680202-G-Achr1-215680202-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_206933.4(USH2A):c.12241C>T(p.Arg4081Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4081Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.72

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Fibronectin type-III 26 (size 85) in uniprot entity USH2A_HUMAN there are 38 pathogenic changes around while only 10 benign (79%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.12241C>T	p.Arg4081Trp	missense_variant	62/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.12241C>T	p.Arg4081Trp	missense_variant	62/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.12241C>T	p.Arg4081Trp	missense_variant	62/73

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251166 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135734

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727230

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74400

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000499

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2022	Identified in a patient with retinitis pigmentosa in published literature, however the individual's second reported USH2A variant is currently classified as benign (Qu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31904091) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 29, 2017	The USH2A p.Arg4081Trp variant (rs144783615) has not been reported in the medical literature. However, the p.Arg4081Trp is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.14% in the African population (identified in 34 out of 24,020 chromosomes), and it is classified as a variant of uncertain significance in ClinVar (Variant ID: 229617). The arginine at codon 4081 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the USH2A protein (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Arg4081Trp variant cannot be determined with certainty. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2016	The p.Arg4081Trp variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 28/121364 chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs144783615). Although this variant has been seen in the general popula tion, its frequency is not high enough to rule out a pathogenic role. Computatio nal prediction tools and conservation analysis suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. In summary, the clinical significance of the p.Arg4081Trp variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2022	Variant summary: USH2A c.12241C>T (p.Arg4081Trp) results in a non-conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251166 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00025 vs 0.011), allowing no conclusion about variant significance. c.12241C>T has been reported in the literature in at least one individual affected with non-syndromic retinitis pigmentosa. This report does not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 2A Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.85
MPC		0.23
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.20
gMVP		0.82

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: rs144783615; hg19: chr1-215853544; COSMIC: COSV100233773;