rs41302133

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_018136.5(ASPM):c.8068C>T(p.Arg2690Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,612,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.466

Publications

8 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021178871).

BP6

Variant 1-197101183-G-A is Benign according to our data. Variant chr1-197101183-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194877.

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.8068C>T	p.Arg2690Trp	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5019C>T		intron	N/A	NP_001193775.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.8068C>T	p.Arg2690Trp	missense	Exon 18 of 28	ENSP00000356379.4
ASPM	ENST00000294732.11	TSL:1	c.4066-5019C>T		intron	N/A	ENSP00000294732.7
ASPM	ENST00000367408.6	TSL:1	n.2108-5019C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000475

AC:

AN:

151630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

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:

0.000354

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000308

AC:

AN:

249686

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000427

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000357

AC:

521

AN:

1460472

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

237

AN XY:

726556

show subpopulations

African (AFR)

AF:

0.000958

AC:

AN:

33408

American (AMR)

AF:

0.000359

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26078

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39620

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000401

AC:

446

AN:

1111246

Other (OTH)

AF:

0.000299

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000494

AC:

AN:

151748

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41454

American (AMR)

AF:

0.000264

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000354

AC:

AN:

67800

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000421

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Microcephaly 5, primary, autosomal recessive (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.66

M_CAP

Benign

0.017

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.47

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.1

REVEL

Benign

0.079

Sift

Uncertain

0.022

Sift4G

Uncertain

0.049

Polyphen

0.29

Vest4

0.27

MVP

0.25

ClinPred

0.030

GERP RS

3.3

Varity_R

0.14

gMVP

0.012

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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