rs199422180

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_018136.5(ASPM):​c.8508_8509delGA​(p.Lys2837MetfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ASPM
NM_018136.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: -0.220

Publications

6 publications found
Variant links:
Genes affected
ASPM (HGNC:19048): (assembly factor for spindle microtubules) This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]
ASPM Gene-Disease associations (from GenCC):
  • microcephaly 5, primary, autosomal recessive
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • autosomal recessive primary microcephaly
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-197100741-TTC-T is Pathogenic according to our data. Variant chr1-197100741-TTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21617.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASPMNM_018136.5 linkc.8508_8509delGA p.Lys2837MetfsTer34 frameshift_variant Exon 18 of 28 ENST00000367409.9 NP_060606.3 Q8IZT6-1B3KWI2
ASPMNM_001206846.2 linkc.4066-4579_4066-4578delGA intron_variant Intron 17 of 26 NP_001193775.1 Q8IZT6-2B3KWI2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkc.8508_8509delGA p.Lys2837MetfsTer34 frameshift_variant Exon 18 of 28 1 NM_018136.5 ENSP00000356379.4 Q8IZT6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000802
AC:
2
AN:
249528
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460610
Hom.:
0
AF XY:
0.00000688
AC XY:
5
AN XY:
726638
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33402
American (AMR)
AF:
0.00
AC:
0
AN:
44556
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39654
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53330
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111294
Other (OTH)
AF:
0.00
AC:
0
AN:
60302
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jul 11, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Segregates in the homozygous state, with primary microcephaly, in many affected individuals from several families in published literature (PMID: 32677750, 14574646); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 38224417, 19028728, 29431480, 14574646, 32677750) -

Microcephaly 5, primary, autosomal recessive Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.22
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs199422180; hg19: chr1-197069871; API