NM_018136.5:c.8711_8712delAA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018136.5(ASPM):c.8711_8712delAA(p.Gln2904ArgfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ASPM
NM_018136.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.121

Publications

1 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-197100538-CTT-C is Pathogenic according to our data. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197100538-CTT-C is described in CliVar as Pathogenic. Clinvar id is 157898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.8711_8712delAA	p.Gln2904ArgfsTer15	frameshift_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-4376_4066-4375delAA		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.8711_8712delAA	p.Gln2904ArgfsTer15	frameshift_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249732

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459630

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

726172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.0000898

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110672

Other (OTH)

AF:

0.00

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151708

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41362

American (AMR)

AF:

0.0000660

AC:

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67814

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln2904Argfs*15) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254). This variant is present in population databases (rs587783283, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with primary autosomal recessive microcephaly (PMID: 23611254). ClinVar contains an entry for this variant (Variation ID: 157898). For these reasons, this variant has been classified as Pathogenic. -

Apr 16, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8711_8712delAA mutation in the ASPM gene has been reported previously as a homozygous mutation in an individual with primary autosomal recessive microcephaly (MCPH) (Tan et al., 2014). The deletion causes a frameshift starting with codon Glutamine 2904, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gln2904ArgfsX15. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.12

Mutation Taster

=3/197

disease causing (ClinVar)

(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