rs41308365

chr1-197101577-G-Achr1-197101577-G-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.7674C>T(p.Ile2558=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,607,148 control chromosomes in the GnomAD database, including 128,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I2558I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (8698 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120117 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.360

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=-0.62).
• BP6: Variant 1-197101577-G-A is Benign according to our data. Variant chr1-197101577-G-A is described in ClinVar as [Benign]. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in Lovd as [Benign]. Variant chr1-197101577-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.7674C>T	p.Ile2558=	synonymous_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-5413C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.7674C>T	p.Ile2558=	synonymous_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 45981 AN: 151364 Hom.: 8702 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.335 AC: 83114 AN: 248176 Hom.: 15547 AF XY: 0.346 AC XY: 46449 AN XY: 134320

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.397 AC: 577479 AN: 1455666 Hom.: 120117 Cov.: 51 AF XY: 0.396 AC XY: 286790 AN XY: 724434

Gnomad4 AFR exome AF: 0.0823

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: 0.371

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.304 AC: 45981 AN: 151482 Hom.: 8698 Cov.: 32 AF XY: 0.299 AC XY: 22132 AN XY: 73982

Gnomad4 AFR AF: 0.0939

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.331

Alfa AF: 0.310 Hom.: 1460

Bravo AF: 0.285

Asia WGS AF: 0.201 AC: 702 AN: 3474

EpiCase AF: 0.421

EpiControl AF: 0.424

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Microcephaly 5, primary, autosomal recessive Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.2
Dann	Benign	0.66

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: rs41308365; hg19: chr1-197070707; COSMIC: COSV54126784;