rs964201

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018136.5(ASPM):c.7480T>C(p.Tyr2494His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,612,646 control chromosomes in the GnomAD database, including 798,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 1.0 ( 75442 hom., cov: 32)

Exomes 𝑓: 0.99 ( 722632 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 3.07

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7361962E-6).

BP6

Variant 1-197101771-A-G is Benign according to our data. Variant chr1-197101771-A-G is described in ClinVar as Benign. ClinVar VariationId is 21599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7480T>C	p.Tyr2494His	missense_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-5607T>C		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.7480T>C	p.Tyr2494His	missense_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.997

AC:

151273

AN:

151780

Hom.:

75383

Cov.:

show subpopulations

Gnomad AFR

AF:

0.999

Gnomad AMI

AF:

0.975

Gnomad AMR

AF:

0.998

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.999

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

0.994

Gnomad OTH

AF:

0.997

GnomAD2 exomes

AF:

0.996

AC:

249662

AN:

250578

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.999

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.998

Gnomad NFE exome

AF:

0.994

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.995

AC:

1452975

AN:

1460748

Hom.:

722632

Cov.:

AF XY:

0.995

AC XY:

722899

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.999

AC:

33393

AN:

33418

American (AMR)

AF:

0.999

AC:

44555

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26091

AN:

26092

East Asian (EAS)

AF:

1.00

AC:

39670

AN:

39670

South Asian (SAS)

AF:

0.997

AC:

85982

AN:

86236

European-Finnish (FIN)

AF:

0.998

AC:

53126

AN:

53230

Middle Eastern (MID)

AF:

1.00

AC:

5762

AN:

5762

European-Non Finnish (NFE)

AF:

0.994

AC:

1104331

AN:

1111412

Other (OTH)

AF:

0.996

AC:

60065

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

501

1002

1503

2004

2505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21664

43328

64992

86656

108320

<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:

0.997

AC:

151391

AN:

151898

Hom.:

75442

Cov.:

AF XY:

0.997

AC XY:

74045

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.999

AC:

41464

AN:

41496

American (AMR)

AF:

0.998

AC:

15156

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3462

AN:

3462

East Asian (EAS)

AF:

1.00

AC:

5137

AN:

5138

South Asian (SAS)

AF:

0.998

AC:

4815

AN:

4826

European-Finnish (FIN)

AF:

0.999

AC:

10623

AN:

10630

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

0.994

AC:

67449

AN:

67844

Other (OTH)

AF:

0.997

AC:

2102

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.996

Hom.:

217364

Bravo

AF:

0.997

TwinsUK

AF:

0.995

AC:

3688

ALSPAC

AF:

0.994

AC:

3830

ESP6500AA

AF:

0.999

AC:

4401

ESP6500EA

AF:

0.994

AC:

8545

ExAC

AF:

0.996

AC:

120856

Asia WGS

AF:

0.998

AC:

3472

AN:

3478

EpiCase

AF:

0.995

EpiControl

AF:

0.995

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

- -

Jul 30, 2012

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 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. -

Microcephaly 5, primary, autosomal recessive

Benign:4Other:1

May 31, 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

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.049

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0000017

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.1

PhyloP100

3.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

2.5

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.14

ClinPred

0.0066

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.041

Mutation Taster

=84/16

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