rs114695225

Variant names:

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.644A>C(p.Glu215Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,142 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 12 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.55

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):

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003560871).

BP6

Variant 1-197143608-T-G is Benign according to our data. Variant chr1-197143608-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136425.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 = 0.00732 (1115/152296) while in subpopulation AFR AF = 0.0255 (1059/41578). AF 95% confidence interval is 0.0242. There are 13 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 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.644A>C	p.Glu215Ala	missense	Exon 3 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.644A>C	p.Glu215Ala	missense	Exon 3 of 27	NP_001193775.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.644A>C	p.Glu215Ala	missense	Exon 3 of 28	ENSP00000356379.4
ASPM	ENST00000294732.11	TSL:1	c.644A>C	p.Glu215Ala	missense	Exon 3 of 27	ENSP00000294732.7
ASPM	ENST00000680265.1		c.644A>C	p.Glu215Ala	missense	Exon 3 of 29	ENSP00000505384.1

Frequencies

GnomAD3 genomes

AF:

0.00731

AC:

1112

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00213

AC:

533

AN:

249678

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000824

AC:

1204

AN:

1460846

Hom.:

Cov.:

AF XY:

0.000706

AC XY:

513

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0264

AC:

885

AN:

33474

American (AMR)

AF:

0.00154

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000151

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52524

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000110

AC:

122

AN:

1111908

Other (OTH)

AF:

0.00172

AC:

104

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

166

249

332

415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00732

AC:

1115

AN:

152296

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0255

AC:

1059

AN:

41578

American (AMR)

AF:

0.00209

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67998

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.00860

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00250

AC:

303

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Microcephaly 5, primary, autosomal recessive (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

1.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.090

Sift

Benign

0.69

Sift4G

Benign

0.37

Polyphen

0.0

Vest4

0.21

MVP

0.42

ClinPred

0.0083

GERP RS

5.2

Varity_R

0.11

gMVP

0.26

Mutation Taster

=97/3

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