rs144049904

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018136.5(ASPM):c.1717C>T(p.Arg573Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,904 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 12 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.81

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008807689).

BP6

Variant 1-197142535-G-A is Benign according to our data. Variant chr1-197142535-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157784.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00208 (317/152188) while in subpopulation AMR AF = 0.007 (107/15296). AF 95% confidence interval is 0.00592. There are 1 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.1717C>T	p.Arg573Trp	missense_variant	Exon 3 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.1717C>T	p.Arg573Trp	missense_variant	Exon 3 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.1717C>T	p.Arg573Trp	missense_variant	Exon 3 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00259

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00190

AC:

476

AN:

251182

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00260

AC:

3804

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

1819

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33476

American (AMR)

AF:

0.00313

AC:

140

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00566

AC:

148

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.000336

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00287

AC:

3190

AN:

1111898

Other (OTH)

AF:

0.00339

AC:

205

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

224

448

672

896

1120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00208

AC:

317

AN:

152188

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

150

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41528

American (AMR)

AF:

0.00700

AC:

107

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00259

AC:

176

AN:

67986

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00254

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00162

AC:

197

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 26, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 08, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASPM: BP4, BS2 -

Microcephaly 5, primary, autosomal recessive

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

ASPM-related disorder

Benign:1

May 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

0.070

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

1.8

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.23

MVP

0.63

ClinPred

0.027

GERP RS

3.2

Varity_R

0.12

gMVP

0.30

Mutation Taster

=98/2

polymorphism

(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