rs6676084

chr1-197124900-C-T

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.3138G>A(p.Arg1046=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,606,914 control chromosomes in the GnomAD database, including 72,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5403 hom., cov: 31)
  • Exomes 𝑓: 0.30 (66773 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.32

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=-0.58).
• BP6: Variant 1-197124900-C-T is Benign according to our data. Variant chr1-197124900-C-T is described in ClinVar as [Benign]. Clinvar id is 21573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197124900-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.3138G>A	p.Arg1046=	synonymous_variant	12/28	ENST00000367409.9
ASPM	NM_001206846.2	c.3138G>A	p.Arg1046=	synonymous_variant	12/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.3138G>A	p.Arg1046=	synonymous_variant	12/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38967 AN: 151770 Hom.: 5398 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.279 AC: 70151 AN: 251118 Hom.: 10449 AF XY: 0.287 AC XY: 38945 AN XY: 135748

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.299 AC: 434446 AN: 1455026 Hom.: 66773 Cov.: 34 AF XY: 0.300 AC XY: 217393 AN XY: 724194

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.143

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.257 AC: 38979 AN: 151888 Hom.: 5403 Cov.: 31 AF XY: 0.255 AC XY: 18929 AN XY: 74214

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.259

Alfa AF: 0.289 Hom.: 3474

Bravo AF: 0.248

Asia WGS AF: 0.214 AC: 743 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.327

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.089
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs6676084; hg19: chr1-197094030; COSMIC: COSV54127589;