rs12677

Positions:

• chr1-197084243-G-A
• chr1-197084243-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018136.5(ASPM):​c.*81C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,029,454 control chromosomes in the GnomAD database, including 408,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (49995 hom., cov: 30)
  • Exomes 𝑓: 0.90 (358008 hom.)
• Consequence: ASPM NM_018136.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.02

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=-0.84).
• BP6: Variant 1-197084243-G-A is Benign according to our data. Variant chr1-197084243-G-A is described in ClinVar as [Benign]. Clinvar id is 294591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
ASPM	NM_018136.5	c.*81C>T		3_prime_UTR_variant	28/28	ENST00000367409.9
ASPM	NM_001206846.2	c.*81C>T		3_prime_UTR_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.*81C>T		3_prime_UTR_variant	28/28	1	NM_018136.5	P1
ASPM	ENST00000294732.11	c.*81C>T		3_prime_UTR_variant	27/27	1
ASPM	ENST00000367408.6	n.3802C>T		non_coding_transcript_exon_variant	18/18	1
ASPM	ENST00000680265.1	c.*81C>T		3_prime_UTR_variant	29/29

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119167 AN: 151916 Hom.: 49972 Cov.: 30

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.814

GnomAD4 exome AF: 0.900 AC: 789604 AN: 877420 Hom.: 358008 Cov.: 11 AF XY: 0.901 AC XY: 412116 AN XY: 457274

Gnomad4 AFR exome AF: 0.450

Gnomad4 AMR exome AF: 0.928

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.900

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.907

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.784 AC: 119240 AN: 152034 Hom.: 49995 Cov.: 30 AF XY: 0.789 AC XY: 58643 AN XY: 74316

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.902

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.899

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.816

Alfa AF: 0.885 Hom.: 50249

Bravo AF: 0.765

Asia WGS AF: 0.919 AC: 3186 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs12677; hg19: chr1-197053373;