rs2878749

Positions:

• chr1-197104802-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018136.5(ASPM):​c.4449A>G​(p.Lys1483=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,577,952 control chromosomes in the GnomAD database, including 127,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8827 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118924 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.911

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-197104802-T-C is Benign according to our data. Variant chr1-197104802-T-C is described in ClinVar as [Benign]. Clinvar id is 21586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197104802-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.4449A>G	p.Lys1483=	synonymous_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-8638A>G		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.4449A>G	p.Lys1483=	synonymous_variant	18/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46275 AN: 151670 Hom.: 8831 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.343 AC: 76809 AN: 224194 Hom.: 14674 AF XY: 0.353 AC XY: 42881 AN XY: 121470

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.399 AC: 569494 AN: 1426164 Hom.: 118924 Cov.: 36 AF XY: 0.398 AC XY: 281737 AN XY: 707482

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.373

GnomAD4 genome AF: 0.305 AC: 46275 AN: 151788 Hom.: 8827 Cov.: 32 AF XY: 0.300 AC XY: 22273 AN XY: 74152

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.330

Alfa AF: 0.405 Hom.: 15202

Bravo AF: 0.286

Asia WGS AF: 0.201 AC: 702 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
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)	Dec 14, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Microcephaly 5, primary, autosomal recessive Benign:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.54
DANN	Benign	0.55

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: rs2878749; hg19: chr1-197073932; COSMIC: COSV54127151;