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

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.20

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38409856).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASPMNM_018136.5 linkc.4496G>T p.Arg1499Leu missense_variant Exon 18 of 28 ENST00000367409.9 NP_060606.3 Q8IZT6-1B3KWI2
ASPMNM_001206846.2 linkc.4066-8591G>T 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.4496G>T p.Arg1499Leu missense_variant Exon 18 of 28 1 NM_018136.5 ENSP00000356379.4 Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.000448
AC:
68
AN:
151794
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00159
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
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
GnomAD2 exomes
AF:
0.000141
AC:
34
AN:
241160
AF XY:
0.0000767
show subpopulations
Gnomad AFR exome
AF:
0.00202
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:
0.00000904
Gnomad OTH exome
AF:
0.000173
GnomAD4 exome
AF:
0.0000414
AC:
60
AN:
1448384
Hom.:
0
Cov.:
38
AF XY:
0.0000431
AC XY:
31
AN XY:
719470
show subpopulations
African (AFR)
AF:
0.00157
AC:
51
AN:
32506
American (AMR)
AF:
0.0000235
AC:
1
AN:
42500
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25614
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39544
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82844
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52956
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5684
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1106960
Other (OTH)
AF:
0.000134
AC:
8
AN:
59776
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
3
6
10
13
16
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
AF:
0.000448
AC:
68
AN:
151912
Hom.:
0
Cov.:
32
AF XY:
0.000391
AC XY:
29
AN XY:
74248
show subpopulations
African (AFR)
AF:
0.00159
AC:
66
AN:
41504
American (AMR)
AF:
0.000132
AC:
2
AN:
15200
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5150
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4810
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67882
Other (OTH)
AF:
0.00
AC:
0
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.522
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000133
Hom.:
1
Bravo
AF:
0.000480
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000148
AC:
18

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Uncertain:3
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 11, 2023
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 23, 2017
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:3
Aug 04, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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). -

Apr 23, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 07, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.088
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.38
T
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
3.8
H
PhyloP100
5.2
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-4.3
D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.81
MVP
0.94
ClinPred
0.86
D
GERP RS
5.5
Varity_R
0.68
gMVP
0.54
Mutation Taster
=68/32
polymorphism

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: rs140119882; hg19: chr1-197073885; API