rs6676084

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.3138G>A(p.Arg1046Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,606,914 control chromosomes in the GnomAD database, including 72,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5403 hom., cov: 31)

Exomes 𝑓: 0.30 ( 66773 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.32

Publications

23 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=-0.58).

BP6

Variant 1-197124900-C-T is Benign according to our data. Variant chr1-197124900-C-T is described in ClinVar as Benign. ClinVar VariationId is 21573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.3138G>A	p.Arg1046Arg	synonymous_variant	Exon 12 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 link	c.3138G>A	p.Arg1046Arg	synonymous_variant	Exon 12 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.3138G>A	p.Arg1046Arg	synonymous_variant	Exon 12 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

38967

AN:

151770

Hom.:

5398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.257

GnomAD2 exomes

AF:

0.279

AC:

70151

AN:

251118

AF XY:

0.287

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.308

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.315

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.299

AC:

434446

AN:

1455026

Hom.:

66773

Cov.:

AF XY:

0.300

AC XY:

217393

AN XY:

724194

show subpopulations

African (AFR)

AF:

0.157

AC:

5241

AN:

33350

American (AMR)

AF:

0.248

AC:

11094

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

8224

AN:

26076

East Asian (EAS)

AF:

0.143

AC:

5656

AN:

39654

South Asian (SAS)

AF:

0.308

AC:

26522

AN:

86098

European-Finnish (FIN)

AF:

0.320

AC:

17103

AN:

53394

Middle Eastern (MID)

AF:

0.349

AC:

1891

AN:

5420

European-Non Finnish (NFE)

AF:

0.309

AC:

341435

AN:

1106172

Other (OTH)

AF:

0.287

AC:

17280

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

15368

30736

46103

61471

76839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10974

21948

32922

43896

54870

<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:

0.257

AC:

38979

AN:

151888

Hom.:

5403

Cov.:

AF XY:

0.255

AC XY:

18929

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.159

AC:

6589

AN:

41444

American (AMR)

AF:

0.253

AC:

3853

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1042

AN:

3462

East Asian (EAS)

AF:

0.125

AC:

649

AN:

5172

South Asian (SAS)

AF:

0.296

AC:

1429

AN:

4822

European-Finnish (FIN)

AF:

0.308

AC:

3244

AN:

10528

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21094

AN:

67908

Other (OTH)

AF:

0.259

AC:

546

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1430

2861

4291

5722

7152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<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:

0.288

Hom.:

3481

Bravo

AF:

0.248

Asia WGS

AF:

0.214

AC:

743

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.327

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

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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. -

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 specified

Benign:3

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

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

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

-0.58

CADD

Benign

0.089

(source)

DANN

Benign

0.60

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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