1-216175261-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_206933.4(USH2A):​c.4618G>A​(p.Asp1540Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1540E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.91
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34488794).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.4618G>A p.Asp1540Asn missense_variant Exon 21 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.4618G>A p.Asp1540Asn missense_variant Exon 21 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.4618G>A p.Asp1540Asn missense_variant Exon 21 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.4618G>A p.Asp1540Asn missense_variant Exon 21 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.4618G>A p.Asp1540Asn missense_variant Exon 21 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250424
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135332
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000547
AC:
80
AN:
1461344
Hom.:
0
Cov.:
31
AF XY:
0.0000495
AC XY:
36
AN XY:
726974
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000648
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 28, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 29, 2024This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1540 of the USH2A protein (p.Asp1540Asn). This variant is present in population databases (rs752238803, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 25472526, 28041643, 36785559). ClinVar contains an entry for this variant (Variation ID: 438022). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsMay 28, 2018- -
USH2A-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 05, 2024The USH2A c.4618G>A variant is predicted to result in the amino acid substitution p.Asp1540Asn. This variant was reported in individuals with retinitis pigmentosa; however, these patients already carried two known pathogenic variants in USH2A (Zhao et al. 2015. PubMed ID: 25472526; supplementary data, Carss et al. 2017. PubMed ID: 28041643). This variant was also described in cis with the c.2276G>T variant in another individual with suspected USH2A-associated disease; an additional causative variant was not identified on the second allele (Reurink et al. 2023. PubMed ID: 36785559). In a large cohort study of individuals with retinal disease, this variant was described as a variant of uncertain significance (supplementary data, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Retinitis pigmentosa Uncertain:1
Uncertain significance, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.094
T;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.79
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.14
Sift
Benign
0.44
T;T
Sift4G
Benign
0.65
T;T
Polyphen
1.0
D;D
Vest4
0.22
MutPred
0.37
Loss of ubiquitination at K1545 (P = 0.0508);Loss of ubiquitination at K1545 (P = 0.0508);
MVP
0.94
MPC
0.19
ClinPred
0.91
D
GERP RS
4.7
Varity_R
0.10
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752238803; hg19: chr1-216348603; COSMIC: COSV56377986; API