rs763909256

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018136.5(ASPM):​c.8266C>T​(p.Gln2756*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,600 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ASPM
NM_018136.5 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.22
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 1-197100985-G-A is Pathogenic according to our data. Variant chr1-197100985-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 522990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASPMNM_018136.5 linkuse as main transcriptc.8266C>T p.Gln2756* stop_gained 18/28 ENST00000367409.9 NP_060606.3 Q8IZT6-1B3KWI2
ASPMNM_001206846.2 linkuse as main transcriptc.4066-4821C>T intron_variant NP_001193775.1 Q8IZT6-2B3KWI2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkuse as main transcriptc.8266C>T p.Gln2756* stop_gained 18/281 NM_018136.5 ENSP00000356379.4 Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
151604
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249576
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134990
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460600
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726622
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000660
AC:
1
AN:
151604
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74008
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardMay 04, 2022The homozygous p.Gln2756Ter variant in ASPM was identified by our study in 2 siblings with autosomal recessive primary microcephaly 5. The variant has not been previously reported in individuals with autosomal recessive primary microcephaly 5, and has been identified in 1 individual by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763909256). This variant has been reported in ClinVar (Variation ID: 522990) as pathogenic by Genomic Research Center, Shahid Beheshti University of Medical Sciences. This nonsense variant leads to a premature termination codon at position 2756, which is predicted to lead to a truncated or absent protein. Loss of function of the ASPM gene is an established disease mechanism in autosomal recessive primary microcephaly 5. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary microcephaly 5 based on the predicted impact of the variant, its absence from control populations, and its homozygous occurrence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2 (Richards 2015). -
Pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesDec 18, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 18, 2019DNA sequence analysis of the ASPM gene demonstrated a sequence change, c.8266C>T, which results in the creation of a premature stop codon at amino acid position 2756, p.Gln2756*, in the apparent homozygous state. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ASPM protein with potentially abnormal function. This pathogenic sequence change has not been reported in the literature and it is present in the gnomAD database with a low population frequency of 0.00041% (dbSNP NA). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.012
FATHMM_MKL
Benign
0.56
D
Vest4
0.61
GERP RS
2.6

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs763909256; hg19: chr1-197070115; API