rs151050191

Variant names:

Variant summary

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

The NM_018136.5(ASPM):c.646G>A(p.Glu216Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,084 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 12 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 3.41

Publications

10 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=0.0067848563).

BP6

Variant 1-197143606-C-T is Benign according to our data. Variant chr1-197143606-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157855.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00104 (1516/1460836) while in subpopulation MID AF = 0.00347 (20/5768). AF 95% confidence interval is 0.0023. There are 12 homozygotes in GnomAdExome4. There are 773 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.646G>A	p.Glu216Lys	missense_variant	Exon 3 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 link	c.646G>A	p.Glu216Lys	missense_variant	Exon 3 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.646G>A	p.Glu216Lys	missense_variant	Exon 3 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00175

AC:

437

AN:

249660

AF XY:

0.00168

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.0310

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000674

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00104

AC:

1516

AN:

1460836

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

773

AN XY:

726754

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.00105

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0330

AC:

863

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52518

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000349

AC:

388

AN:

1111908

Other (OTH)

AF:

0.00308

AC:

186

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00135

AC:

206

AN:

152248

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41570

American (AMR)

AF:

0.00177

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000530

AC:

AN:

67968

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00153

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00120

AC:

146

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Uncertain:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:2

Feb 12, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Mar 27, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

ASPM-related disorder

Benign:1

May 28, 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

0.080

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

2.0

M;M

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.054

T;T

Polyphen

0.031

B;.

Vest4

0.30

MVP

0.61

ClinPred

0.033

GERP RS

5.2

Varity_R

0.24

gMVP

0.44

Mutation Taster

=96/4

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