rs33987824

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018136.5(ASPM):c.2751C>T(p.Ala917Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,611,552 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 13 hom., cov: 32)

Exomes 𝑓: 0.018 ( 305 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.721

Publications

3 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=-0.48).

BP6

Variant 1-197129196-G-A is Benign according to our data. Variant chr1-197129196-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.721 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0134 (2039/152112) while in subpopulation NFE AF = 0.0201 (1366/67958). AF 95% confidence interval is 0.0192. There are 13 homozygotes in GnomAd4. There are 970 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.2751C>T	p.Ala917Ala	synonymous_variant	Exon 9 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.2751C>T	p.Ala917Ala	synonymous_variant	Exon 9 of 27		NP_001193775.1	Q8IZT6-2B3KWI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.2751C>T	p.Ala917Ala	synonymous_variant	Exon 9 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2041

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00346

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.00862

GnomAD2 exomes

AF:

0.0149

AC:

3753

AN:

251078

AF XY:

0.0156

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.00559

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0180

AC:

26238

AN:

1459440

Hom.:

305

Cov.:

AF XY:

0.0176

AC XY:

12808

AN XY:

726100

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

33436

American (AMR)

AF:

0.00537

AC:

240

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

807

AN:

26082

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39532

South Asian (SAS)

AF:

0.0105

AC:

904

AN:

85964

European-Finnish (FIN)

AF:

0.0211

AC:

1124

AN:

53386

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0198

AC:

21985

AN:

1110320

Other (OTH)

AF:

0.0170

AC:

1027

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

1221

2443

3664

4886

6107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.0134

AC:

2039

AN:

152112

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

970

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00345

AC:

143

AN:

41502

American (AMR)

AF:

0.00694

AC:

106

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00892

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0238

AC:

252

AN:

10580

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0201

AC:

1366

AN:

67958

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0179

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0171

EpiControl

AF:

0.0185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 02, 2014

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Benign:2

Jan 12, 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. -

Apr 11, 2023

Genome-Nilou Lab

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

-0.48

CADD

Benign

6.2

(source)

DANN

Benign

0.66

PhyloP100

-0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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