rs36004306

chr1-197091956-A-Cchr1-197091956-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018136.5(ASPM):c.9395T>G(p.Leu3132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,611,488 control chromosomes in the GnomAD database, including 1,621 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3132P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (144 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1477 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033656657).
• BP6: Variant 1-197091956-A-C is Benign according to our data. Variant chr1-197091956-A-C is described in ClinVar as [Benign]. Clinvar id is 21625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197091956-A-C is described in Lovd as [Benign]. Variant chr1-197091956-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.9395T>G	p.Leu3132Arg	missense_variant	22/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4640T>G	p.Leu1547Arg	missense_variant	21/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.9395T>G	p.Leu3132Arg	missense_variant	22/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4934 AN: 152000 Hom.: 144 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.0379

GnomAD3 exomes AF: 0.0345 AC: 8640 AN: 250620 Hom.: 185 AF XY: 0.0352 AC XY: 4772 AN XY: 135436

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.0368

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0422 AC: 61520 AN: 1459370 Hom.: 1477 Cov.: 31 AF XY: 0.0419 AC XY: 30423 AN XY: 726048

Gnomad4 AFR exome AF: 0.00710

Gnomad4 AMR exome AF: 0.0384

Gnomad4 ASJ exome AF: 0.0470

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.0474

Gnomad4 OTH exome AF: 0.0377

GnomAD4 genome AF: 0.0324 AC: 4933 AN: 152118 Hom.: 144 Cov.: 32 AF XY: 0.0308 AC XY: 2290 AN XY: 74388

Gnomad4 AFR AF: 0.00857

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0490

Gnomad4 OTH AF: 0.0375

Alfa AF: 0.0425 Hom.: 182

Bravo AF: 0.0322

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0478 AC: 411

ExAC AF: 0.0341 AC: 4142

EpiCase AF: 0.0448

EpiControl AF: 0.0476

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	This 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. -

Microcephaly 5, primary, autosomal recessive Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Benign, for Microcephaly 5, primary, autosomal recessive. The following ACMG Tag(s) were applied: BP1 => Missense in gene where only truncating cause disease. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BS2 => Allele frequency is greater than expected for disorder. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	10
Dann	Benign	0.85
DEOGEN2	Benign	0.090	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.072	T;T;T
Polyphen		0.35	B;.;.
Vest4		0.13
ClinPred		0.010	T
GERP RS		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs36004306; hg19: chr1-197061086; COSMIC: COSV54135152;