dbSNP rs587783217: ASPM:p.Met401Val (chr1-197143051-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018136.5(ASPM):c.1201A>G(p.Met401Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

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):

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055728048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.1201A>G	p.Met401Val	missense_variant	Exon 3 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 link	c.1201A>G	p.Met401Val	missense_variant	Exon 3 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.1201A>G	p.Met401Val	missense_variant	Exon 3 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111184

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.028

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.0030

B;.

Vest4

0.19

MutPred

0.24

Loss of disorder (P = 0.0707);Loss of disorder (P = 0.0707);

MVP

0.20

ClinPred

0.088

GERP RS

3.2

Varity_R

0.13

gMVP

0.16

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over