NM_018136.5:c.9395T>G

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.9395T>G(p.Leu3132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,611,488 control chromosomes in the GnomAD database, including 1,621 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3132P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.032 ( 144 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1477 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.30

Publications

18 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):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
microcephaly 5, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

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=0.0033656657).

BP6

Variant 1-197091956-A-C is Benign according to our data. Variant chr1-197091956-A-C is described in ClinVar as Benign. ClinVar VariationId is 21625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.9395T>G	p.Leu3132Arg	missense	Exon 22 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4640T>G	p.Leu1547Arg	missense	Exon 21 of 27	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.9395T>G	p.Leu3132Arg	missense	Exon 22 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.4640T>G	p.Leu1547Arg	missense	Exon 21 of 27	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000367408.6	TSL:1	n.2682T>G		non_coding_transcript_exon	Exon 12 of 18

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4934

AN:

152000

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00862

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0430

Gnomad ASJ

AF:

0.0522

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.0177

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.0379

GnomAD2 exomes

AF:

0.0345

AC:

8640

AN:

250620

AF XY:

0.0352

show subpopulations

Gnomad AFR exome

AF:

0.00782

Gnomad AMR exome

AF:

0.0368

Gnomad ASJ exome

AF:

0.0465

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.0477

Gnomad OTH exome

AF:

0.0421

GnomAD4 exome

AF:

0.0422

AC:

61520

AN:

1459370

Hom.:

1477

Cov.:

AF XY:

0.0419

AC XY:

30423

AN XY:

726048

show subpopulations

African (AFR)

AF:

0.00710

AC:

237

AN:

33384

American (AMR)

AF:

0.0384

AC:

1713

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

1224

AN:

26068

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39572

South Asian (SAS)

AF:

0.0240

AC:

2067

AN:

86176

European-Finnish (FIN)

AF:

0.0196

AC:

1044

AN:

53370

Middle Eastern (MID)

AF:

0.0556

AC:

285

AN:

5126

European-Non Finnish (NFE)

AF:

0.0474

AC:

52676

AN:

1110790

Other (OTH)

AF:

0.0377

AC:

2271

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2963

5925

8888

11850

14813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1904

3808

5712

7616

9520

<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:

0.0324

AC:

4933

AN:

152118

Hom.:

144

Cov.:

AF XY:

0.0308

AC XY:

2290

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00857

AC:

356

AN:

41540

American (AMR)

AF:

0.0430

AC:

654

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.0522

AC:

181

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5166

South Asian (SAS)

AF:

0.0184

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0177

AC:

188

AN:

10620

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0490

AC:

3332

AN:

67958

Other (OTH)

AF:

0.0375

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

230

460

691

921

1151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0422

Hom.:

453

Bravo

AF:

0.0322

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0449

AC:

173

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0478

AC:

411

ExAC

AF:

0.0341

AC:

4142

EpiCase

AF:

0.0448

EpiControl

AF:

0.0476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Microcephaly 5, primary, autosomal recessive (4)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.090

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

2.3

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.33

Sift

Benign

0.20

Sift4G

Benign

0.072

Polyphen

0.35

Vest4

0.13

ClinPred

0.010

GERP RS

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.16

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over