rs10922162

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018136.5(ASPM):c.7605G>A(p.Val2535Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,611,328 control chromosomes in the GnomAD database, including 39,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3836 hom., cov: 33)

Exomes 𝑓: 0.19 ( 35971 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.171

Publications

29 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 -21 ACMG points.

BP4

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

BP6

Variant 1-197101646-C-T is Benign according to our data. Variant chr1-197101646-C-T is described in ClinVar as Benign. ClinVar VariationId is 21603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.171 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7605G>A	p.Val2535Val	synonymous_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 link	c.4066-5482G>A		intron_variant	Intron 17 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.7605G>A	p.Val2535Val	synonymous_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26596

AN:

151548

Hom.:

3827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.334

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.695

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.257

AC:

64162

AN:

249682

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.0395

Gnomad AMR exome

AF:

0.465

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.706

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.217

GnomAD4 exome

AF:

0.192

AC:

280881

AN:

1459662

Hom.:

35971

Cov.:

AF XY:

0.194

AC XY:

140694

AN XY:

726200

show subpopulations

African (AFR)

AF:

0.0336

AC:

1121

AN:

33410

American (AMR)

AF:

0.455

AC:

20257

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4676

AN:

26076

East Asian (EAS)

AF:

0.684

AC:

27116

AN:

39648

South Asian (SAS)

AF:

0.277

AC:

23840

AN:

86216

European-Finnish (FIN)

AF:

0.241

AC:

12689

AN:

52754

Middle Eastern (MID)

AF:

0.131

AC:

755

AN:

5758

European-Non Finnish (NFE)

AF:

0.160

AC:

177853

AN:

1110936

Other (OTH)

AF:

0.209

AC:

12574

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

12374

24748

37121

49495

61869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6742

13484

20226

26968

33710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.175

AC:

26609

AN:

151666

Hom.:

3836

Cov.:

AF XY:

0.188

AC XY:

13906

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.0419

AC:

1735

AN:

41450

American (AMR)

AF:

0.335

AC:

5075

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

660

AN:

3458

East Asian (EAS)

AF:

0.696

AC:

3558

AN:

5114

South Asian (SAS)

AF:

0.305

AC:

1470

AN:

4826

European-Finnish (FIN)

AF:

0.249

AC:

2627

AN:

10550

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.162

AC:

10978

AN:

67796

Other (OTH)

AF:

0.196

AC:

412

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

976

1951

2927

3902

4878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.166

Hom.:

11949

Bravo

AF:

0.180

Asia WGS

AF:

0.478

AC:

1660

AN:

3478

EpiCase

AF:

0.164

EpiControl

AF:

0.155

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Benign:4Other:1

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

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 06, 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. -

not specified

Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Dec 17, 2013

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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.64

(source)

DANN

Benign

0.64

PhyloP100

0.17

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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