1-197084420-CT-C

Position:

• chr1-197084420-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_018136.5(ASPM):​c.10337del​(p.Lys3446SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,446,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ASPM NM_018136.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.97

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 3456 codons.
• PP5: Variant 1-197084420-CT-C is Pathogenic according to our data. Variant chr1-197084420-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 503777.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.10337del	p.Lys3446SerfsTer6	frameshift_variant	28/28	ENST00000367409.9
ASPM	NM_001206846.2	c.5582del	p.Lys1861SerfsTer6	frameshift_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.10337del	p.Lys3446SerfsTer6	frameshift_variant	28/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446656 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 720422

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: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2017

The c.10337delA variant in the ASPM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It is not observed in large population cohorts (Lek et al., 2016). The c.10337delA variant causes a frameshift starting with codon Lysine 3446, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Lys3446SerfsX6. This variant is predicted to cause loss of normal protein function through protein truncation as 32 amino acids of the protein are replaced with 5 incorrect amino acids. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot becompletely excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553325275; hg19: chr1-197053550;