rs17550662

Positions:

• chr1-197139816-A-G

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.1977T>C​(p.Ile659=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,611,814 control chromosomes in the GnomAD database, including 2,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (178 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2545 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.10

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=-0.54).
• BP6: Variant 1-197139816-A-G is Benign according to our data. Variant chr1-197139816-A-G is described in ClinVar as [Benign]. Clinvar id is 21561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197139816-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.1977T>C	p.Ile659=	synonymous_variant	4/28	ENST00000367409.9
ASPM	NM_001206846.2	c.1977T>C	p.Ile659=	synonymous_variant	4/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.1977T>C	p.Ile659=	synonymous_variant	4/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6236 AN: 152176 Hom.: 178 Cov.: 33

Gnomad AFR AF: 0.00902

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0636

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0444 AC: 11155 AN: 251442 Hom.: 336 AF XY: 0.0452 AC XY: 6146 AN XY: 135886

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0589

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0543 AC: 79216 AN: 1459520 Hom.: 2545 Cov.: 31 AF XY: 0.0533 AC XY: 38730 AN XY: 726170

Gnomad4 AFR exome AF: 0.00763

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0621

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0789

Gnomad4 NFE exome AF: 0.0612

Gnomad4 OTH exome AF: 0.0504

GnomAD4 genome AF: 0.0409 AC: 6236 AN: 152294 Hom.: 178 Cov.: 33 AF XY: 0.0392 AC XY: 2916 AN XY: 74472

Gnomad4 AFR AF: 0.00902

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.0614

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0559 Hom.: 169

Bravo AF: 0.0380

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0683

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephaly 5, primary, autosomal recessive Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.3
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17550662; hg19: chr1-197108946;