rs748331272

Variant names:

Variant summary

Our verdict is The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2PM4_Supporting

The NM_018136.5(ASPM):c.567_569delGAG (p.Arg189del) variant causes a disruptive inframe deletion change. The variant results in an in-frame change. The variant allele was found at a cumulative frequency of 0.00000248 (AC=4) in the gnomAD database across 1,613,686 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ASPM
NM_018136.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.82

Publications

0 publications found

Variant links:

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: ClinGen, Orphanet
microcephaly 5, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ASPM links:

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new If you want to explore the variant's impact on the transcript NM_018136.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 points.

PM2

Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000147 — very rare for AR gene (threshold 0.001) — PM2 moderate.

PM4

Single amino-acid in-frame indel in non-repetitive region — protein length change, supporting (PM4 +1); In-frame indel in non-repetitive region — protein length change (1 AA).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.567_569delGAG	p.Arg189del	disruptive_inframe_deletion	Exon 3 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.567_569delGAG	p.Arg189del	disruptive_inframe_deletion	Exon 3 of 27	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.567_569delGAG	p.Arg189del	disruptive_inframe_deletion	Exon 3 of 28	ENSP00000356379.4	Q8IZT6-1
ASPM	ENST00000294732.11	TSL:1	c.567_569delGAG	p.Arg189del	disruptive_inframe_deletion	Exon 3 of 27	ENSP00000294732.7	Q8IZT6-2
ASPM	ENST00000680265.1		c.567_569delGAG	p.Arg189del	disruptive_inframe_deletion	Exon 3 of 29	ENSP00000505384.1	A0A7P0Z491

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.00000658	1	0	152084	33
GnomAD2 exomes	0.00000399	1		250412
GnomAD4 exome	0.00000205	3	0	1461602
GnomAD4 genome	0.00000658	1	0	152084	33
TOPMed (Bravo)	0.00000756
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0000742	1	0	13470

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
Epi25 (Epilepsy)	0.0000238	1	41958	0.00	0	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
Mutation Taster	N/A	polymorphism	80/20
PhyloP100	Uncertain	-	5.8

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over