chr1-197128485-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_018136.5(ASPM):c.2936+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_018136.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPM | NM_018136.5 | c.2936+5G>A | splice_region_variant, intron_variant | ENST00000367409.9 | NP_060606.3 | |||
ASPM | NM_001206846.2 | c.2936+5G>A | splice_region_variant, intron_variant | NP_001193775.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPM | ENST00000367409.9 | c.2936+5G>A | splice_region_variant, intron_variant | 1 | NM_018136.5 | ENSP00000356379.4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251214Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455954Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 724826
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74276
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2017 | The c.2936+5 G>A variant in the ASPM gene has been observed as a homozygous variant (reported as c.2936 +5 G>T in Table 1) in a consanguineous Pakistani family with congenital microcephaly (Bond et al., 2003). The c.2936+5 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). It alters a position that is conserved across species. In silico splice prediction models suggest that the c.2936+5 G>A variant may damage the natural splice donor site of intron 10. However, in the absence of RNA/functional studies, the effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be completely excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at