rs36004306

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.032 ( 144 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1477 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.9395T>G	p.Leu3132Arg	missense_variant	22/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.4640T>G	p.Leu1547Arg	missense_variant	21/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.9395T>G	p.Leu3132Arg	missense_variant	22/28	1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4934

AN:

152000

Hom.:

144

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0419

AC XY:

30423

AN XY:

726048

show subpopulations

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.:

AF XY:

0.0308

AC XY:

2290

AN XY:

74388

show subpopulations

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:

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:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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. -
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, 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	-	- -

Microcephaly 5, primary, autosomal recessive

Benign:3Other: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:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.090

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over