8-61503378-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_004318.4(ASPH):c.2258G>A(p.Arg753His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,605,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R753L) has been classified as Uncertain significance.
Frequency
Consequence
NM_004318.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPH | ENST00000379454.9 | c.2258G>A | p.Arg753His | missense_variant | Exon 25 of 25 | 1 | NM_004318.4 | ENSP00000368767.4 | ||
ASPH | ENST00000541428.5 | c.2171G>A | p.Arg724His | missense_variant | Exon 25 of 25 | 2 | ENSP00000437864.1 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000320 AC: 78AN: 243966Hom.: 0 AF XY: 0.000303 AC XY: 40AN XY: 132018
GnomAD4 exome AF: 0.000574 AC: 834AN: 1453552Hom.: 0 Cov.: 29 AF XY: 0.000556 AC XY: 402AN XY: 722688
GnomAD4 genome AF: 0.000197 AC: 30AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74338
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.2258G>A (p.R753H) alteration is located in exon 25 (coding exon 25) of the ASPH gene. This alteration results from a G to A substitution at nucleotide position 2258, causing the arginine (R) at amino acid position 753 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 753 of the ASPH protein (p.Arg753His). This variant is present in population databases (rs141861375, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ASPH-related conditions. ClinVar contains an entry for this variant (Variation ID: 2358987). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at