rs587783291

chr1-197091899-A-C

Variant summary

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

The NM_018136.5(ASPM):c.9444+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,609,224 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003181
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.84

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=-0.85).
• BP6: Variant 1-197091899-A-C is Benign according to our data. Variant chr1-197091899-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 157912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00256 (389/152162) while in subpopulation AFR AF= 0.00903 (375/41544). AF 95% confidence interval is 0.00827. There are 3 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.9444+8T>G		splice_region_variant, intron_variant		ENST00000367409.9
ASPM	NM_001206846.2	c.4689+8T>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.9444+8T>G		splice_region_variant, intron_variant		1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152044 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00903

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000635 AC: 159 AN: 250230 Hom.: 3 AF XY: 0.000503 AC XY: 68 AN XY: 135282

Gnomad AFR exome AF: 0.00870

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000258 AC: 376 AN: 1457062 Hom.: 3 Cov.: 31 AF XY: 0.000229 AC XY: 166 AN XY: 724890

Gnomad4 AFR exome AF: 0.00907

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000500

GnomAD4 genome AF: 0.00256 AC: 389 AN: 152162 Hom.: 3 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74398

Gnomad4 AFR AF: 0.00903

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000938 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2018	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	Eurofins Ntd Llc (ga)	May 27, 2015	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ASPM: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Microcephaly 5, primary, autosomal recessive Benign:2

Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.72
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs140150599; hg19: chr1-197061029;