chr1-197104755-C-A
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4
The NM_018136.5(ASPM):c.4496G>T(p.Arg1499Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00008 in 1,600,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_018136.5 missense
Scores
Clinical Significance
Conservation
Publications
- microcephaly 5, primary, autosomal recessiveInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive primary microcephalyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000448 AC: 68AN: 151794Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000141 AC: 34AN: 241160 AF XY: 0.0000767 show subpopulations
GnomAD4 exome AF: 0.0000414 AC: 60AN: 1448384Hom.: 0 Cov.: 38 AF XY: 0.0000431 AC XY: 31AN XY: 719470 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000448 AC: 68AN: 151912Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 29AN XY: 74248 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Microcephaly 5, primary, autosomal recessive Uncertain:3
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not provided Uncertain:3
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 not expected to disrupt ASPM 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. ClinVar contains an entry for this variant (Variation ID: 157823). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1499 of the ASPM protein (p.Arg1499Leu). This variant is present in population databases (rs140119882, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of ASPM-related conditions (PMID: 23611254). -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at