rs147100928

Positions:

• chr1-197102534-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_018136.5(ASPM):​c.6717G>C​(p.Leu2239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,612,484 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (3 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.176

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-197102534-C-G is Benign according to our data. Variant chr1-197102534-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157856.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}. Variant chr1-197102534-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.176 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.6717G>C	p.Leu2239=	synonymous_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-6370G>C		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.6717G>C	p.Leu2239=	synonymous_variant	18/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 151796 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000744 AC: 186 AN: 249870 Hom.: 0 AF XY: 0.000763 AC XY: 103 AN XY: 135074

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000949 AC: 1386 AN: 1460570 Hom.: 3 Cov.: 41 AF XY: 0.000911 AC XY: 662 AN XY: 726592

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151914 Hom.: 0 Cov.: 33 AF XY: 0.000619 AC XY: 46 AN XY: 74254

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000789

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000938 Hom.: 0

Bravo AF: 0.000710

EpiCase AF: 0.00202

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ASPM: BP4, BP7 -

Microcephaly 5, primary, autosomal recessive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.7
DANN	Benign	0.54

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: rs147100928; hg19: chr1-197071664;