rs41299587

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018136.5(ASPM):c.3742-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,610,884 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 88 hom. )

Consequence

ASPM
NM_018136.5 intron

Scores

Splicing: ADA: 0.0009193

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.18

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 5, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive primary microcephaly
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ASPM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 1-197122053-A-C is Benign according to our data. Variant chr1-197122053-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 157809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00645 (982/152280) while in subpopulation NFE AF = 0.0101 (684/68004). AF 95% confidence interval is 0.00943. There are 7 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.3742-10T>G		intron_variant	Intron 15 of 27	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.3742-10T>G		intron_variant	Intron 15 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.3742-10T>G		intron_variant	Intron 15 of 27	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00645

AC:

981

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00705

AC:

1741

AN:

247014

AF XY:

0.00702

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.00602

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00378

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00998

GnomAD4 exome

AF:

0.00966

AC:

14094

AN:

1458604

Hom.:

Cov.:

AF XY:

0.00942

AC XY:

6834

AN XY:

725664

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

33378

American (AMR)

AF:

0.00614

AC:

273

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

538

AN:

26076

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39562

South Asian (SAS)

AF:

0.00114

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.00368

AC:

196

AN:

53190

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0112

AC:

12389

AN:

1109786

Other (OTH)

AF:

0.00878

AC:

529

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

728

1455

2183

2910

3638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00645

AC:

982

AN:

152280

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41568

American (AMR)

AF:

0.00726

AC:

111

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

684

AN:

68004

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00811

Hom.:

Bravo

AF:

0.00680

Asia WGS

AF:

0.00144

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Benign:4

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Sep 21, 2015

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 specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 01, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASPM: BS1, BS2 -

Apr 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ASPM-related disorder

Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.53

PhyloP100

2.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00092

dbscSNV1_RF

Benign

0.34

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs41299587

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over