rs4915337

chr1-197122407-A-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.3579T>A(p.Ser1193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,613,582 control chromosomes in the GnomAD database, including 641,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (49988 hom., cov: 32)
  • Exomes 𝑓: 0.90 (591199 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.295

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=-0.85).
• BP6: Variant 1-197122407-A-T is Benign according to our data. Variant chr1-197122407-A-T is described in ClinVar as [Benign]. Clinvar id is 21578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122407-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.3579T>A	p.Ser1193=	synonymous_variant	14/28	ENST00000367409.9
ASPM	NM_001206846.2	c.3579T>A	p.Ser1193=	synonymous_variant	14/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.3579T>A	p.Ser1193=	synonymous_variant	14/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119166 AN: 152002 Hom.: 49965 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.814

GnomAD3 exomes AF: 0.887 AC: 222653 AN: 250926 Hom.: 100699 AF XY: 0.894 AC XY: 121249 AN XY: 135624

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.899

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.896 AC: 1309791 AN: 1461462 Hom.: 591199 Cov.: 58 AF XY: 0.898 AC XY: 652601 AN XY: 727040

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.929

Gnomad4 ASJ exome AF: 0.899

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.899

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.904

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.784 AC: 119239 AN: 152120 Hom.: 49988 Cov.: 32 AF XY: 0.789 AC XY: 58651 AN XY: 74374

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.898

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.816

Alfa AF: 0.902 Hom.: 47170

Bravo AF: 0.765

Asia WGS AF: 0.920 AC: 3198 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.909

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

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	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
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	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	-0.85
Cadd	Benign	4.5
Dann	Benign	0.53

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: rs4915337; hg19: chr1-197091537;