chr9-92457338-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_017680.6(ASPN):c.1093C>T(p.Arg365Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Consequence
NM_017680.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPN | ENST00000375544.7 | c.1093C>T | p.Arg365Cys | missense_variant | Exon 8 of 8 | 1 | ENSP00000364694.3 | |||
CENPP | ENST00000375587.8 | c.564+77479G>A | intron_variant | Intron 5 of 7 | 1 | NM_001012267.3 | ENSP00000364737.3 | |||
ASPN | ENST00000375543 | c.*128C>T | 3_prime_UTR_variant | Exon 6 of 6 | 2 | ENSP00000364693.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251268Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135784
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461718Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727162
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
The ASPN p.Arg365Cys variant was not identified in the literature nor was it identified in dbSNP, ClinVar, or LOVD 3.0. The variant was identified in Cosmic where the reported FATHMM prediction was pathogenic (score 0.99). The variant was also identified in control databases in 1 of 251268 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Other population in 1 of 6128 chromosomes (freq: 0.000163), but not in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Arg365 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster, AlignGVGD) 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at