rs199422138

Variant names:

• chr1-197143072-TA-T
• rs199422138
• NM_018136.5:c.1179delT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018136.5(ASPM):​c.1179delT​(p.Asn394IlefsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ASPM NM_018136.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: -0.180

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 Pathogenic. Variant got 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 1-197143072-TA-T is Pathogenic according to our data. Variant chr1-197143072-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 21551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197143072-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.1179delT	p.Asn394IlefsTer4	frameshift_variant	Exon 3 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.1179delT	p.Asn394IlefsTer4	frameshift_variant	Exon 3 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.1179delT	p.Asn394IlefsTer4	frameshift_variant	Exon 3 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460722 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 27, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with microcephaly (Nicholas et al., 2009); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19028728, 20301772) -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn394Ilefs*4) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary microcephaly (PMID: 19028728). This variant is also known as p.Pro393fs. ClinVar contains an entry for this variant (Variation ID: 21551). For these reasons, this variant has been classified as Pathogenic. -

Microcephaly 5, primary, autosomal recessive Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs199422138; hg19: chr1-197112202;