rs6677082

chr1-197143403-G-Achr1-197143403-G-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.849C>T(p.Ser283=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,613,648 control chromosomes in the GnomAD database, including 637,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (48504 hom., cov: 32)
  • Exomes 𝑓: 0.89 (588703 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.223

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 1-197143403-G-A is Benign according to our data. Variant chr1-197143403-G-A is described in ClinVar as [Benign]. Clinvar id is 95890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197143403-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.849C>T	p.Ser283=	synonymous_variant	3/28	ENST00000367409.9
ASPM	NM_001206846.2	c.849C>T	p.Ser283=	synonymous_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.849C>T	p.Ser283=	synonymous_variant	3/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115899 AN: 151960 Hom.: 48487 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.798

GnomAD3 exomes AF: 0.880 AC: 221090 AN: 251178 Hom.: 99775 AF XY: 0.889 AC XY: 120681 AN XY: 135820

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.982

Gnomad SAS exome AF: 0.898

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.896

GnomAD4 exome AF: 0.893 AC: 1305661 AN: 1461570 Hom.: 588703 Cov.: 57 AF XY: 0.895 AC XY: 650758 AN XY: 727090

Gnomad4 AFR exome AF: 0.360

Gnomad4 AMR exome AF: 0.925

Gnomad4 ASJ exome AF: 0.899

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.904

Gnomad4 OTH exome AF: 0.877

GnomAD4 genome AF: 0.762 AC: 115957 AN: 152078 Hom.: 48504 Cov.: 32 AF XY: 0.768 AC XY: 57125 AN XY: 74368

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.864

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.898

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.800

Alfa AF: 0.843 Hom.: 34735

Bravo AF: 0.741

Asia WGS AF: 0.909 AC: 3161 AN: 3478

EpiCase AF: 0.905

EpiControl AF: 0.909

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2014	- -

Microcephaly 5, primary, autosomal recessive Benign:4

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	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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	-0.84
Cadd	Benign	5.5
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4

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: rs6677082; hg19: chr1-197112533;