rs41299623

Positions:

chr1-197104066-G-A

Variant summary

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

The NM_018136.5(ASPM):c.5185C>T(p.Arg1729Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,612,828 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 100 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.85

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:

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=0.004125327).

BP6

Variant 1-197104066-G-A is Benign according to our data. Variant chr1-197104066-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197104066-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00827 (1257/151970) while in subpopulation AMR AF= 0.0148 (225/15214). AF 95% confidence interval is 0.0132. There are 11 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.5185C>T	p.Arg1729Trp	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.4066-7902C>T		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.5185C>T	p.Arg1729Trp	missense_variant	18/28	1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00828

AC:

1257

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0165

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0173

GnomAD3 exomes

AF:

0.00955

AC:

2390

AN:

250290

Hom.:

AF XY:

0.0101

AC XY:

1360

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.000762

Gnomad SAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.00219

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.00979

AC:

14307

AN:

1460858

Hom.:

100

Cov.:

AF XY:

0.0101

AC XY:

7330

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.0190

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0125

Gnomad4 FIN exome

AF:

0.00267

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.00827

AC:

1257

AN:

151970

Hom.:

Cov.:

AF XY:

0.00818

AC XY:

608

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.0165

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00912

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00844

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00963

AC:

1169

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ASPM: PM5, BP4, BS1, BS2 -

Microcephaly 5, primary, autosomal recessive

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2013	- -

ASPM-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.39

MVP

0.33

ClinPred

0.083

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.40

gMVP

0.089

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