chr1-197143114-G-A

Variant names:

• chr1-197143114-G-A
• rs587783215
• NM_018136.5:c.1138C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018136.5(ASPM):​c.1138C>T​(p.Gln380*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASPM NM_018136.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.124
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197143114-G-A is Pathogenic according to our data. Variant chr1-197143114-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 157777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.1138C>T	p.Gln380*	stop_gained	Exon 3 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.1138C>T	p.Gln380*	stop_gained	Exon 3 of 27	NP_001193775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.1138C>T	p.Gln380*	stop_gained	Exon 3 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.1138C>T	p.Gln380*	stop_gained	Exon 3 of 27	ENSP00000294732.7
	ASPM	ENST00000680265.1		c.1138C>T	p.Gln380*	stop_gained	Exon 3 of 29	ENSP00000505384.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000249 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Pathogenic:7

Oct 30, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Gln380Ter variant in ASPM was identified by our study in 2 siblings with autosomal recessive primary microcephaly 5. The variant has been reported in 1 Middle Eastern individual with autosomal recessive primary microcephaly 5 (PMID: 23611254), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 157777) as pathogenic by Genetic Services Laboratory, University of Chicago and Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, and as likely pathogenic by Developmental Genetics Unit, King Faisal Specialist Hospital & Research Centre. This nonsense variant leads to a premature termination codon at position 380, which is predicted to lead to a truncated or absent protein. Loss of function of the ASPM gene is an established disease mechanism in autosomal recessive primary microcephaly 5. The presence of this variant in at least 2 homozygotes, and in 2 individuals with autosomal recessive primary microcephaly 5 increases the likelihood that the p.Gln380Ter variant is pathogenic (PMID: 23611254). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive primary microcephaly 5 based on the predicted impact of the variant, its absence from control populations, and its homozygous appearance in 3 affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Aug 25, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.068	N
PhyloP100		0.12
Vest4		0.56
GERP RS		0.70
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783215; hg19: chr1-197112244;