rs41299623

Variant names:

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.5185C>T(p.Arg1729Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,612,828 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1729Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0083 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 100 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.85

Publications

22 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:

ENSG00000300054 (HGNC:):

ENSG00000300054 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 (MetaRNN=0.004125327).

BP6

Variant 1-197104066-G-A is Benign according to our data. Variant chr1-197104066-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00827 (1257/151970) while in subpopulation AMR AF = 0.0148 (225/15214). AF 95% confidence interval is 0.0132. There are 11 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.5185C>T	p.Arg1729Trp	missense_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-7902C>T		intron_variant	Intron 17 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.5185C>T	p.Arg1729Trp	missense_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00828

AC:

1257

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0165

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.00955

AC:

2390

AN:

250290

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.000762

Gnomad FIN exome

AF:

0.00219

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.00979

AC:

14307

AN:

1460858

Hom.:

100

Cov.:

AF XY:

0.0101

AC XY:

7330

AN XY:

726756

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

33430

American (AMR)

AF:

0.0109

AC:

485

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

497

AN:

26104

East Asian (EAS)

AF:

0.000479

AC:

AN:

39674

South Asian (SAS)

AF:

0.0125

AC:

1074

AN:

86228

European-Finnish (FIN)

AF:

0.00267

AC:

142

AN:

53166

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5764

European-Non Finnish (NFE)

AF:

0.0102

AC:

11302

AN:

1111512

Other (OTH)

AF:

0.0102

AC:

614

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

919

1839

2758

3678

4597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00827

AC:

1257

AN:

151970

Hom.:

Cov.:

AF XY:

0.00818

AC XY:

608

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41514

American (AMR)

AF:

0.0148

AC:

225

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.00912

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

794

AN:

67896

Other (OTH)

AF:

0.0171

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

130

196

261

326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0100

Hom.:

Bravo

AF:

0.00844

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00963

AC:

1169

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASPM: PM5, BP4, BS1, BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jul 03, 2013

Eurofins Ntd Llc (ga)

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

- -

Dec 05, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Benign:3

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 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

- -

ASPM-related disorder

Benign:1

Mar 25, 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.7

PhyloP100

2.8

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.39

MVP

0.33

ClinPred

0.083

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.40

gMVP

0.089

Mutation Taster

=86/14

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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rs41299623

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