rs41299623

chr1-197104066-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1729Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (100 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.85

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.5185C>T	p.Arg1729Trp	missense_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-7902C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.5185C>T	p.Arg1729Trp	missense_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1257 AN: 151852 Hom.: 11 Cov.: 32

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.: 16 AF XY: 0.0101 AC XY: 1360 AN XY: 135278

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.: 38 AF XY: 0.0101 AC XY: 7330 AN XY: 726756

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.: 11 Cov.: 32 AF XY: 0.00818 AC XY: 608 AN XY: 74292

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.: 25

Bravo AF: 0.00844

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00963 AC: 1169

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ASPM: PM5, BP4, BS1, BS2 -

Microcephaly 5, primary, autosomal recessive Benign:3

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. -
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	- -

not specified Benign:2

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

ASPM-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.33
ClinPred		0.083	T
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

Other links and lift over

dbSNP: rs41299623; hg19: chr1-197073196; COSMIC: COSV99038474;