rs33987824

chr1-197129196-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018136.5(ASPM):c.2751C>T(p.Ala917=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,611,552 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (305 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.721

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=-0.48).
• BP6: Variant 1-197129196-G-A is Benign according to our data. Variant chr1-197129196-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197129196-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.721 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2039/152112) while in subpopulation NFE AF= 0.0201 (1366/67958). AF 95% confidence interval is 0.0192. There are 13 homozygotes in gnomad4. There are 970 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.2751C>T	p.Ala917=	synonymous_variant	9/28	ENST00000367409.9
ASPM	NM_001206846.2	c.2751C>T	p.Ala917=	synonymous_variant	9/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.2751C>T	p.Ala917=	synonymous_variant	9/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2041 AN: 151994 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0149 AC: 3753 AN: 251078 Hom.: 36 AF XY: 0.0156 AC XY: 2116 AN XY: 135694

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00979

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0180 AC: 26238 AN: 1459440 Hom.: 305 Cov.: 31 AF XY: 0.0176 AC XY: 12808 AN XY: 726100

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.0309

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0134 AC: 2039 AN: 152112 Hom.: 13 Cov.: 32 AF XY: 0.0130 AC XY: 970 AN XY: 74358

Gnomad4 AFR AF: 0.00345

Gnomad4 AMR AF: 0.00694

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0194 Hom.: 13

Bravo AF: 0.0116

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0171

EpiControl AF: 0.0185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2014	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	PreventionGenetics, part of Exact Sciences	-	- -

Microcephaly 5, primary, autosomal recessive Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	6.2
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs33987824; hg19: chr1-197098326; COSMIC: COSV54129985;