rs1537318

Positions:

• chr1-197084264-G-A
• chr1-197084264-G-T

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.*60C>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 0.00471 in 1,258,850 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (69 hom.)
• Consequence: ASPM NM_018136.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.47

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]

ASPM (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-197084264-G-A is Benign according to our data. Variant chr1-197084264-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.*60C>T		3_prime_UTR_variant	28/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.*60C>T		3_prime_UTR_variant	27/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409	c.*60C>T		3_prime_UTR_variant	28/28	1	NM_018136.5	ENSP00000356379.4
ASPM	ENST00000294732	c.*60C>T		3_prime_UTR_variant	27/27	1		ENSP00000294732.7
ASPM	ENST00000367408.6	n.3781C>T		non_coding_transcript_exon_variant	18/18	1
ASPM	ENST00000680265	c.*60C>T		3_prime_UTR_variant	29/29			ENSP00000505384.1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3166 AN: 151806 Hom.: 96 Cov.: 31

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00821

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00249 AC: 2760 AN: 1106926 Hom.: 69 Cov.: 15 AF XY: 0.00215 AC XY: 1218 AN XY: 566476

Gnomad4 AFR exome AF: 0.0735

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000796

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.000373

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.0209 AC: 3173 AN: 151924 Hom.: 96 Cov.: 31 AF XY: 0.0198 AC XY: 1472 AN XY: 74232

Gnomad4 AFR AF: 0.0720

Gnomad4 AMR AF: 0.00819

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00293 Hom.: 7

Bravo AF: 0.0232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Benign:2

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.68
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: rs1537318; hg19: chr1-197053394;