chr17-74919578-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS1
The NM_173477.5(USH1G):c.1258C>G(p.Leu420Val) variant causes a missense change. The variant allele was found at a frequency of 0.00188 in 1,612,640 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L420L) has been classified as Likely benign.
Frequency
Consequence
NM_173477.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1G | NM_173477.5 | c.1258C>G | p.Leu420Val | missense_variant | 2/3 | ENST00000614341.5 | |
USH1G | NM_001282489.3 | c.949C>G | p.Leu317Val | missense_variant | 2/3 | ||
USH1G | XM_011524296.2 | c.949C>G | p.Leu317Val | missense_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1G | ENST00000614341.5 | c.1258C>G | p.Leu420Val | missense_variant | 2/3 | 1 | NM_173477.5 | P1 | |
USH1G | ENST00000579243.1 | c.*857C>G | 3_prime_UTR_variant, NMD_transcript_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000874 AC: 133AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000937 AC: 233AN: 248630Hom.: 1 AF XY: 0.000895 AC XY: 121AN XY: 135250
GnomAD4 exome AF: 0.00199 AC: 2900AN: 1460424Hom.: 6 Cov.: 41 AF XY: 0.00195 AC XY: 1417AN XY: 726500
GnomAD4 genome ? AF: 0.000874 AC: 133AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:6Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 19, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The USH1G p.Leu420Val variant was identified as a heterozygous variant in 1 of 340 proband chromosomes (frequency: 0.00294) from an individual with Usher syndrome, however two pathogenic variants in the USH2A gene (p.C3090*, p.W3702*) were identified in this individual and were presumed to be the cause of disease (Glockle_2014_PMID:23591405). The variant was identified in dbSNP (ID: rs139897506), ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and EGL Genetic Diagnostics), and LOVD 3.0 (conflicting classifications). The variant was identified in control databases in 258 of 280002 chromosomes (1 homozygous) at a frequency of 0.0009214 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 215 of 127098 chromosomes (freq: 0.001692), Other in 5 of 7168 chromosomes (freq: 0.000698), European (Finnish) in 14 of 25108 chromosomes (freq: 0.000558), African in 10 of 24562 chromosomes (freq: 0.000407), Latino in 10 of 35374 chromosomes (freq: 0.000283) and South Asian in 4 of 30562 chromosomes (freq: 0.000131), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2020 | This variant is associated with the following publications: (PMID: 23591405, 26878454) - |
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 | Eurofins Ntd Llc (ga) | Apr 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the USH1G protein (p.Leu420Val). This variant is present in population databases (rs139897506, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with USH1G-related conditions. ClinVar contains an entry for this variant (Variation ID: 48126). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH1G 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 21, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Leu420Val var iant in USH1G has now been identified in 2 individuals with Usher syndrome and 5 individuals with hearing loss. One of the individuals with Usher syndrome had t wo pathogenic variants in another gene which explained the disease (Glockle 2014 ). A variant affecting the remaining copy of USH1G was not detected in any of th e other individuals (LMM data). This variant has been identified in 0.2% (109/62 876) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs139897506). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. Computational prediction tools and conservation analyses do not provi de strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Leu420Val variant is uncertain, these data sugge st that it is more likely to be benign. - |
Usher syndrome type 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
USH1G-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 18, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at