1-197101685-T-C

Position:

• chr1-197101685-T-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.7566A>G​(p.Leu2522Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,612,026 control chromosomes in the GnomAD database, including 645,630 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. L2522L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (52044 hom., cov: 32)
  • Exomes 𝑓: 0.90 (593586 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.356

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]

ASPM (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-197101685-T-C is Benign according to our data. Variant chr1-197101685-T-C is described in ClinVar as [Benign]. Clinvar id is 21602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101685-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.356 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	Protein	UniProt
ASPM	NM_018136.5	c.7566A>G	p.Leu2522Leu	synonymous_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-5521A>G		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.7566A>G	p.Leu2522Leu	synonymous_variant	18/28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123089 AN: 151598 Hom.: 52003 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.834

GnomAD3 exomes AF: 0.895 AC: 223759 AN: 249892 Hom.: 101432 AF XY: 0.900 AC XY: 121616 AN XY: 135128

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.907

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: 0.904

GnomAD4 exome AF: 0.899 AC: 1313541 AN: 1460310 Hom.: 593586 Cov.: 69 AF XY: 0.900 AC XY: 654203 AN XY: 726508

Gnomad4 AFR exome AF: 0.535

Gnomad4 AMR exome AF: 0.935

Gnomad4 ASJ exome AF: 0.913

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: 0.891

GnomAD4 genome AF: 0.812 AC: 123184 AN: 151716 Hom.: 52044 Cov.: 32 AF XY: 0.815 AC XY: 60432 AN XY: 74166

Gnomad4 AFR AF: 0.547

Gnomad4 AMR AF: 0.884

Gnomad4 ASJ AF: 0.915

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.899

Gnomad4 FIN AF: 0.928

Gnomad4 NFE AF: 0.911

Gnomad4 OTH AF: 0.836

Alfa AF: 0.885 Hom.: 64783

Bravo AF: 0.798

Asia WGS AF: 0.929 AC: 3228 AN: 3476

EpiCase AF: 0.906

EpiControl AF: 0.910

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
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	-	- -

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	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.52
DANN	Benign	0.55

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: rs1412640; hg19: chr1-197070815;