rs77138363

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018136.5(ASPM):c.5579C>T(p.Ala1860Val) variant causes a missense change. The variant allele was found at a frequency of 0.00315 in 1,612,742 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1860A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 50 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 49 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.54

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 links:

ASPM (HGNC:):

ASPM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008574486).

BP6

Variant 1-197103672-G-A is Benign according to our data. Variant chr1-197103672-G-A is described in ClinVar as [Benign]. Clinvar id is 157836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197103672-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2155/151946) while in subpopulation AFR AF= 0.046 (1910/41484). AF 95% confidence interval is 0.0443. There are 50 homozygotes in gnomad4. There are 1032 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.5579C>T	p.Ala1860Val	missense_variant	18/28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 linkuse as main transcript	c.4066-7508C>T		intron_variant			NP_001193775.1	Q8IZT6-2B3KWI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.5579C>T	p.Ala1860Val	missense_variant	18/28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2152

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0461

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00645

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0205

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00815

GnomAD3 exomes

AF:

0.00501

AC:

1249

AN:

249192

Hom.:

AF XY:

0.00385

AC XY:

519

AN XY:

134704

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00279

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0180

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000330

Gnomad OTH exome

AF:

0.00314

GnomAD4 exome

AF:

0.00200

AC:

2920

AN:

1460796

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1317

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.0459

Gnomad4 AMR exome

AF:

0.00296

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0177

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.0142

AC:

2155

AN:

151946

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1032

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0460

Gnomad4 AMR

AF:

0.00644

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0204

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00346

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00568

AC:

689

Asia WGS

AF:

0.00751

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Microcephaly 5, primary, autosomal recessive

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0086

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.35

Sift

Benign

0.046

Sift4G

Uncertain

0.019

Polyphen

0.99

Vest4

0.32

MVP

0.88

ClinPred

0.066

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.076

gMVP

0.085

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over