rs77191836

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018136.5(ASPM):​c.2419+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,599,632 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 28 hom., cov: 32)
Exomes 𝑓: 0.020 ( 314 hom. )

Consequence

ASPM
NM_018136.5 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.718
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 1-197133338-C-T is Benign according to our data. Variant chr1-197133338-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197133338-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2725/152228) while in subpopulation NFE AF= 0.0212 (1444/67994). AF 95% confidence interval is 0.0203. There are 28 homozygotes in gnomad4. There are 1277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASPMNM_018136.5 linkuse as main transcriptc.2419+12G>A intron_variant ENST00000367409.9 NP_060606.3
ASPMNM_001206846.2 linkuse as main transcriptc.2419+12G>A intron_variant NP_001193775.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkuse as main transcriptc.2419+12G>A intron_variant 1 NM_018136.5 ENSP00000356379 P1Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.0179
AC:
2728
AN:
152110
Hom.:
28
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0166
Gnomad AMI
AF:
0.0186
Gnomad AMR
AF:
0.0162
Gnomad ASJ
AF:
0.0153
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0143
Gnomad FIN
AF:
0.0153
Gnomad MID
AF:
0.0316
Gnomad NFE
AF:
0.0212
Gnomad OTH
AF:
0.0163
GnomAD3 exomes
AF:
0.0162
AC:
3913
AN:
241242
Hom.:
35
AF XY:
0.0164
AC XY:
2132
AN XY:
130380
show subpopulations
Gnomad AFR exome
AF:
0.0170
Gnomad AMR exome
AF:
0.0102
Gnomad ASJ exome
AF:
0.0162
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.0155
Gnomad FIN exome
AF:
0.0114
Gnomad NFE exome
AF:
0.0214
Gnomad OTH exome
AF:
0.0199
GnomAD4 exome
AF:
0.0195
AC:
28253
AN:
1447404
Hom.:
314
Cov.:
31
AF XY:
0.0192
AC XY:
13833
AN XY:
718606
show subpopulations
Gnomad4 AFR exome
AF:
0.0170
Gnomad4 AMR exome
AF:
0.0112
Gnomad4 ASJ exome
AF:
0.0156
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0158
Gnomad4 FIN exome
AF:
0.0120
Gnomad4 NFE exome
AF:
0.0214
Gnomad4 OTH exome
AF:
0.0195
GnomAD4 genome
AF:
0.0179
AC:
2725
AN:
152228
Hom.:
28
Cov.:
32
AF XY:
0.0172
AC XY:
1277
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0165
Gnomad4 AMR
AF:
0.0162
Gnomad4 ASJ
AF:
0.0153
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.0145
Gnomad4 FIN
AF:
0.0153
Gnomad4 NFE
AF:
0.0212
Gnomad4 OTH
AF:
0.0161
Alfa
AF:
0.0182
Hom.:
4
Bravo
AF:
0.0182
Asia WGS
AF:
0.00577
AC:
20
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 13, 2014This 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. -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
Microcephaly 5, primary, autosomal recessive Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
1.5
DANN
Benign
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs77191836; hg19: chr1-197102468; API