rs193251130

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018136.5(ASPM):ā€‹c.9539A>Cā€‹(p.Gln3180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,386 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0013 ( 8 hom., cov: 32)
Exomes š‘“: 0.0023 ( 105 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: 0.150
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.032000035).
BP6
Variant 1-197090947-T-G is Benign according to our data. Variant chr1-197090947-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Benign=6, Uncertain_significance=1}. Variant chr1-197090947-T-G is described in Lovd as [Likely_benign]. Variant chr1-197090947-T-G is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00129 (196/152240) while in subpopulation SAS AF= 0.0377 (182/4822). AF 95% confidence interval is 0.0333. There are 8 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASPMNM_018136.5 linkuse as main transcriptc.9539A>C p.Gln3180Pro missense_variant 23/28 ENST00000367409.9 NP_060606.3
ASPMNM_001206846.2 linkuse as main transcriptc.4784A>C p.Gln1595Pro missense_variant 22/27 NP_001193775.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkuse as main transcriptc.9539A>C p.Gln3180Pro missense_variant 23/281 NM_018136.5 ENSP00000356379 P1Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.00131
AC:
199
AN:
152122
Hom.:
8
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0381
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.00467
AC:
1171
AN:
250508
Hom.:
35
AF XY:
0.00616
AC XY:
834
AN XY:
135344
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0370
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.00180
GnomAD4 exome
AF:
0.00228
AC:
3334
AN:
1461146
Hom.:
105
Cov.:
32
AF XY:
0.00326
AC XY:
2372
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0359
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000522
Gnomad4 OTH exome
AF:
0.00240
GnomAD4 genome
AF:
0.00129
AC:
196
AN:
152240
Hom.:
8
Cov.:
32
AF XY:
0.00188
AC XY:
140
AN XY:
74428
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0377
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000364
Hom.:
0
Bravo
AF:
0.000298
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00502
AC:
610
Asia WGS
AF:
0.0190
AC:
66
AN:
3476
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:9Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:5
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 28, 2018- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024ASPM: BP4, BS1, BS2 -
Microcephaly 5, primary, autosomal recessive Uncertain:1Benign:2Other:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
not provided, no classification providedliterature onlyGeneReviews-- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitterresearchBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard-The homozygous p.Gln3180Pro variant in ASPM has been identified in 4 siblings from 1 family with primary microcephaly (PMID: 16673149), and has been identified in >3% of South Asian chromosomes and 19 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive primary microcephaly. -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 07, 2017- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 22, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.34
N
LIST_S2
Benign
0.79
T;T;T
MetaRNN
Benign
0.032
T;T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Uncertain
2.5
M;.;.
MutationTaster
Benign
1.2e-10
A;A;A
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Benign
0.28
Sift
Benign
0.065
T;D;D
Sift4G
Uncertain
0.032
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.49
MVP
0.48
ClinPred
0.041
T
GERP RS
2.6
Varity_R
0.34
gMVP
0.37

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: rs193251130; hg19: chr1-197060077; API