rs115594989

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_018136.5(ASPM):c.4436A>G(p.Lys1479Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,580,280 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.101

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):

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033749342).

BP6

Variant 1-197104815-T-C is Benign according to our data. Variant chr1-197104815-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210357.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00105 (159/152098) while in subpopulation AFR AF = 0.00373 (155/41552). AF 95% confidence interval is 0.00325. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4436A>G	p.Lys1479Arg	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-8651A>G		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.4436A>G	p.Lys1479Arg	missense	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.4066-8651A>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000367408.6	TSL:1	n.2108-8651A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

159

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.000240

AC:

AN:

225126

AF XY:

0.000172

show subpopulations

Gnomad AFR exome

AF:

0.00330

Gnomad AMR exome

AF:

0.0000352

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000946

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.0000931

AC:

133

AN:

1428182

Hom.:

Cov.:

AF XY:

0.0000819

AC XY:

AN XY:

708548

show subpopulations

African (AFR)

AF:

0.00378

AC:

119

AN:

31462

American (AMR)

AF:

0.0000788

AC:

AN:

38052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24720

East Asian (EAS)

AF:

0.00

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

79862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098444

Other (OTH)

AF:

0.000153

AC:

AN:

58870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.00105

AC:

159

AN:

152098

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00373

AC:

155

AN:

41552

American (AMR)

AF:

0.000263

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67930

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000215

Hom.:

Bravo

AF:

0.00106

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Microcephaly 5, primary, autosomal recessive (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.4

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.70

M_CAP

Benign

0.015

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.28

PhyloP100

-0.10

PrimateAI

Benign

0.22

PROVEAN

Benign

0.16

REVEL

Benign

0.099

Sift

Benign

0.74

Sift4G

Benign

1.0

Polyphen

0.48

Vest4

0.053

MVP

0.43

ClinPred

0.023

GERP RS

-1.3

Varity_R

0.057

gMVP

0.024

Mutation Taster

=92/8

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