rs62624968

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5063C>T(p.Thr1688Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,612,518 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. T1688A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 48 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 49 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.53

Publications

7 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:

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=0.002592057).

BP6

Variant 1-197104188-G-A is Benign according to our data. Variant chr1-197104188-G-A is described in ClinVar as Benign. ClinVar VariationId is 157827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2152/151948) while in subpopulation AFR AF = 0.046 (1910/41482). AF 95% confidence interval is 0.0443. There are 48 homozygotes in GnomAd4. There are 1028 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

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.5063C>T	p.Thr1688Ile	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-8024C>T		intron	N/A	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.5063C>T	p.Thr1688Ile	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.4066-8024C>T		intron	N/A	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000367408.6	TSL:1	n.2108-8024C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2149

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0461

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00631

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0201

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00497

AC:

1240

AN:

249388

AF XY:

0.00381

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00198

AC:

2892

AN:

1460570

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

1305

AN XY:

726578

show subpopulations

African (AFR)

AF:

0.0458

AC:

1531

AN:

33396

American (AMR)

AF:

0.00294

AC:

131

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.0177

AC:

700

AN:

39596

South Asian (SAS)

AF:

0.000162

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000220

AC:

245

AN:

1111384

Other (OTH)

AF:

0.00428

AC:

258

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

168

336

504

672

840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.0142

AC:

2152

AN:

151948

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1028

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0460

AC:

1910

AN:

41482

American (AMR)

AF:

0.00631

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.0200

AC:

103

AN:

5156

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000324

AC:

AN:

67882

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00356

Hom.:

Bravo

AF:

0.0151

ESP6500AA

AF:

0.0438

AC:

193

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00563

AC:

683

Asia WGS

AF:

0.00751

AC:

AN:

3476

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Microcephaly 5, primary, autosomal recessive (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.3

(source)

DANN

Benign

0.073

DEOGEN2

Benign

0.014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.069

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.7

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

1.4

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

0.99

Polyphen

0.0

Vest4

0.039

MVP

0.25

ClinPred

0.0054

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.016

gMVP

0.0095

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over