rs150062050
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BS1_SupportingBS2
The NM_000147.5(FUCA1):c.433T>C(p.Trp145Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,614,226 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000147.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00128 AC: 195AN: 152222Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00110 AC: 276AN: 251490Hom.: 2 AF XY: 0.00121 AC XY: 165AN XY: 135922
GnomAD4 exome AF: 0.00154 AC: 2255AN: 1461886Hom.: 5 Cov.: 32 AF XY: 0.00152 AC XY: 1109AN XY: 727242
GnomAD4 genome AF: 0.00127 AC: 194AN: 152340Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:3
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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The FUCA1 p.Trp145Arg variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs150062050), ClinVar (classified as a VUS by Illumina Clinical Services, Invitae, and Fulgent Genetics for Fucosidosis), and LOVD 3.0. The variant was identified in control databases in 301 of 282896 chromosomes (2 homozygous) at a frequency of 0.001064 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 224 of 129196 chromosomes (freq: 0.001734), South Asian in 38 of 30616 chromosomes (freq: 0.001241), Other in 6 of 7226 chromosomes (freq: 0.00083), Latino in 19 of 35440 chromosomes (freq: 0.000536), African in 10 of 24970 chromosomes (freq: 0.000401), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193) and European (Finnish) in 2 of 25124 chromosomes (freq: 0.00008); it was not observed in the East Asian population. The p.Trp145 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Fucosidosis Uncertain:2Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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FUCA1-related disorder Benign:1
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). -
Intellectual disability Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at