rs41310925

chr1-197103290-T-Cchr1-197103290-T-G

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.5961A>G(p.Gln1987=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,612,890 control chromosomes in the GnomAD database, including 129,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8815 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120943 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.90

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=-0.9).
• BP6: Variant 1-197103290-T-C is Benign according to our data. Variant chr1-197103290-T-C is described in ClinVar as [Benign]. Clinvar id is 21593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197103290-T-C is described in Lovd as [Benign]. Variant chr1-197103290-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.89 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	UniProt
ASPM	NM_018136.5	c.5961A>G	p.Gln1987=	synonymous_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-7126A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.5961A>G	p.Gln1987=	synonymous_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46036 AN: 151720 Hom.: 8819 Cov.: 32

Gnomad AFR AF: 0.0888

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.331

GnomAD3 exomes AF: 0.335 AC: 83931 AN: 250246 Hom.: 15837 AF XY: 0.346 AC XY: 46823 AN XY: 135244

Gnomad AFR exome AF: 0.0830

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.433

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.397 AC: 580747 AN: 1461052 Hom.: 120943 Cov.: 51 AF XY: 0.397 AC XY: 288248 AN XY: 726844

Gnomad4 AFR exome AF: 0.0760

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.303 AC: 46035 AN: 151838 Hom.: 8815 Cov.: 32 AF XY: 0.299 AC XY: 22177 AN XY: 74224

Gnomad4 AFR AF: 0.0886

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.329

Alfa AF: 0.389 Hom.: 6363

Bravo AF: 0.284

Asia WGS AF: 0.202 AC: 706 AN: 3476

EpiCase AF: 0.422

EpiControl AF: 0.426

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
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. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.12
Dann	Benign	0.30

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: rs41310925; hg19: chr1-197072420; COSMIC: COSV54124262;