rs765530357

Variant names:

• chr1-197101665-CTGATA-C
• rs765530357
• NM_018136.5:c.7581_7585delTATCA

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.7581_7585delTATCA​(p.Tyr2527fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,242 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: 0.0000048 (0 hom.)
• Consequence: ASPM NM_018136.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.608
• Publications: 0 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):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

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 1-197101665-CTGATA-C is Pathogenic according to our data. Variant chr1-197101665-CTGATA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 522025.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.7581_7585delTATCA	p.Tyr2527fs	frameshift	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5506_4066-5502delTATCA		intron	N/A	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.7581_7585delTATCA	p.Tyr2527fs	frameshift	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5506_4066-5502delTATCA		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5506_2108-5502delTATCA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249762 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460242 Hom.: 0 AF XY: 0.00000826 AC XY: 6 AN XY: 726446

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.0000224 AC: 1 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111252

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765530357; hg19: chr1-197070795;