NM_018136.5:c.7566A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018136.5(ASPM):c.7566A>G(p.Leu2522Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,612,026 control chromosomes in the GnomAD database, including 645,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2522L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.81 ( 52044 hom., cov: 32)

Exomes 𝑓: 0.90 ( 593586 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.356

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-197101685-T-C is Benign according to our data. Variant chr1-197101685-T-C is described in ClinVar as [Benign]. Clinvar id is 21602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101685-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.356 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7566A>G	p.Leu2522Leu	synonymous_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-5521A>G		intron_variant	Intron 17 of 26		NP_001193775.1	Q8IZT6-2B3KWI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.7566A>G	p.Leu2522Leu	synonymous_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123089

AN:

151598

Hom.:

52003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.955

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.915

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.898

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.911

Gnomad OTH

AF:

0.834

GnomAD3 exomes

AF:

0.895

AC:

223759

AN:

249892

Hom.:

101432

AF XY:

0.900

AC XY:

121616

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.939

Gnomad ASJ exome

AF:

0.907

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.899

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.906

Gnomad OTH exome

AF:

0.904

GnomAD4 exome

AF:

0.899

AC:

1313541

AN:

1460310

Hom.:

593586

Cov.:

AF XY:

0.900

AC XY:

654203

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.535

Gnomad4 AMR exome

AF:

0.935

Gnomad4 ASJ exome

AF:

0.913

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.899

Gnomad4 FIN exome

AF:

0.932

Gnomad4 NFE exome

AF:

0.904

Gnomad4 OTH exome

AF:

0.891

GnomAD4 genome

AF:

0.812

AC:

123184

AN:

151716

Hom.:

52044

Cov.:

AF XY:

0.815

AC XY:

60432

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.547

Gnomad4 AMR

AF:

0.884

Gnomad4 ASJ

AF:

0.915

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.899

Gnomad4 FIN

AF:

0.928

Gnomad4 NFE

AF:

0.911

Gnomad4 OTH

AF:

0.836

Alfa

AF:

0.885

Hom.:

64783

Bravo

AF:

0.798

Asia WGS

AF:

0.929

AC:

3228

AN:

3476

EpiCase

AF:

0.906

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Benign:4Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.52

DANN

Benign

0.55

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.

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