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):

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=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.

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.7480T>C	p.Tyr2494His	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5607T>C		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.7480T>C	p.Tyr2494His	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.4066-5607T>C		intron	N/A	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000367408.6	TSL:1	n.2108-5607T>C		intron	N/A

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

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 (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over