rs143275144
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_206933.4(USH2A):āc.14519T>Cā(p.Leu4840Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000396 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L4840L) has been classified as Likely benign.
Frequency
Genomes: š 0.00033 ( 0 hom., cov: 32)
Exomes š: 0.00040 ( 1 hom. )
Consequence
USH2A
NM_206933.4 missense
NM_206933.4 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 4.41
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 2 ACMG points.
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.14519T>C | p.Leu4840Pro | missense_variant | 66/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.14519T>C | p.Leu4840Pro | missense_variant | 66/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.14519T>C | p.Leu4840Pro | missense_variant | 66/73 |
Frequencies
GnomAD3 genomes ? AF: 0.000335 AC: 51AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000306 AC: 77AN: 251294Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135822
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GnomAD4 exome AF: 0.000402 AC: 588AN: 1461876Hom.: 1 Cov.: 31 AF XY: 0.000408 AC XY: 297AN XY: 727244
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GnomAD4 genome ? AF: 0.000335 AC: 51AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74474
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2022 | Reported as homozygous variant in a patient with Usher syndrome, with another variant, C1900G, in cis on both alleles (Bonnet et al., 2016); Observed in a patient with retinitis pigmentosa in published literature (McGee et al., 2010); 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: 24944099, 27460420, 20507924) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4840 of the USH2A protein (p.Leu4840Pro). This variant is present in population databases (rs143275144, gnomAD 0.04%). This missense change has been observed in individual(s) with retinal disease (PMID: 20507924; Invitae). ClinVar contains an entry for this variant (Variation ID: 48442). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Usher syndrome type 2A Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 20, 2018 | This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 26, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 20, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Leu4840Pro variant in USH2A has been previously reported by our laboratory in 2 individuals with hearing loss who each carried different homozygous pathogenic variants in another gene that explained the hearing loss. This variant has also been reported in 3 individuals with either retinitis pigmentosa or Usher syndrome. It was homozygous in 1 individual, but a variant affecting the remaining copy of USH2A was not identified in the other 2 individuals (McGee 2010, Baux 2014, Bonnet 2016). It has also been identified in 0.05% (59/129026) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 48442) .The leucine (Leu) at position 4840 is not highly conserved in mammals and evolutionary distant species, and two mammals (prairie vole and Golden hamster) have a proline (Pro) at the position, supporting that this change at this position may be tolerated. In summary, while the clinical significance of the p.Leu4804Pro variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2_Supporting, PP4, PM3_Supporting, BP4. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 24, 2022 | - - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology ā Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Supporting, PP3_Supporting - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 06, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at