rs139367209

chr1-197105038-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.4213C>T(p.Arg1405Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00556 in 1,610,098 control chromosomes in the GnomAD database, including 59 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. R1405H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (52 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.48

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=0.013116419).
• BP6: Variant 1-197105038-G-A is Benign according to our data. Variant chr1-197105038-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 157818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197105038-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00427 (648/151880) while in subpopulation SAS AF= 0.0162 (78/4818). AF 95% confidence interval is 0.0133. There are 7 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.4213C>T	p.Arg1405Cys	missense_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-8874C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.4213C>T	p.Arg1405Cys	missense_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 644 AN: 151762 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00244

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00645

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00521 AC: 1301 AN: 249482 Hom.: 11 AF XY: 0.00600 AC XY: 810 AN XY: 134908

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00899

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.000839

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00570 AC: 8310 AN: 1458218 Hom.: 52 Cov.: 33 AF XY: 0.00608 AC XY: 4406 AN XY: 725060

Gnomad4 AFR exome AF: 0.000600

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00887

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00476

GnomAD4 genome AF: 0.00427 AC: 648 AN: 151880 Hom.: 7 Cov.: 32 AF XY: 0.00395 AC XY: 293 AN XY: 74230

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00244

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00645

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00583 Hom.: 10

Bravo AF: 0.00373

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00549 AC: 667

EpiCase AF: 0.00548

EpiControl AF: 0.00635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ASPM: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2018	- -

Microcephaly 5, primary, autosomal recessive Benign:3

Likely 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	Dec 15, 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:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2016	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	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 02, 2016	- -

ASPM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2020

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	0.16
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.31
MVP		0.98
ClinPred		0.093	T
GERP RS		4.3
Varity_R		0.71
gMVP		0.35

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: rs139367209; hg19: chr1-197074168; COSMIC: COSV54126719;