rs587783235

Positions:

• chr1-197122053-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000367409.9(ASPM):​c.3742-10T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,610,884 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (88 hom.)
• Consequence: ASPM ENST00000367409.9 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009193
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-197122053-A-C is Benign according to our data. Variant chr1-197122053-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 157809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122053-A-C is described in Lovd as [Likely_benign]. Variant chr1-197122053-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00645 (982/152280) while in subpopulation NFE AF= 0.0101 (684/68004). AF 95% confidence interval is 0.00943. There are 7 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.3742-10T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.3742-10T>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.3742-10T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 981 AN: 152162 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00705 AC: 1741 AN: 247014 Hom.: 13 AF XY: 0.00702 AC XY: 940 AN XY: 133858

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.00378

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00998

GnomAD4 exome AF: 0.00966 AC: 14094 AN: 1458604 Hom.: 88 Cov.: 32 AF XY: 0.00942 AC XY: 6834 AN XY: 725664

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00614

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00368

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00878

GnomAD4 genome AF: 0.00645 AC: 982 AN: 152280 Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74466

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00816 Hom.: 3

Bravo AF: 0.00680

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2016	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	Nov 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ASPM: BS1, BS2 -

ASPM-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41299587; hg19: chr1-197091183;