NM_018136.4:c.567_569del

Variant names:

• chr1-197143682-GCTC-G
• rs748331272
• NM_018136.5:c.567_569delGAG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• 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: ClinGen, Orphanet
• microcephaly 5, primary, autosomal recessive

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		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.
	PM4Protein length change in non-repeat region		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	Prot: NP_060606.3
	ASPM NM_001206846.2		c.567_569delGAG p.Arg189del	disruptive_inframe_deletion	Exon 3 of 27	Prot: NP_001193775.1 UniProt:

ASPM NM_018136.5

MANE Select

HGVSc / HGVSpc.567_569delGAGp.Arg189del

Exon rankExon 3 of 28

disruptive_inframe_deletion

Prot: NP_060606.3

ASPM NM_001206846.2

HGVSc / HGVSpc.567_569delGAGp.Arg189del

Exon rankExon 3 of 27

disruptive_inframe_deletion

Prot: NP_001193775.1UniProt: Q8IZT6-2

Ensembl Transcripts

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

ASPM ENST00000367409.9

TSL:1MANE Select

HGVSc / HGVSpc.567_569delGAGp.Arg189del

Exon rankExon 3 of 28

disruptive_inframe_deletion

Prot: ENSP00000356379.4UniProt: Q8IZT6-1

ASPM ENST00000294732.11

TSL:1

HGVSc / HGVSpc.567_569delGAGp.Arg189del

Exon rankExon 3 of 27

disruptive_inframe_deletion

Prot: ENSP00000294732.7UniProt: Q8IZT6-2

ASPM ENST00000680265.1

HGVSc / HGVSpc.567_569delGAGp.Arg189del

Exon rankExon 3 of 29

disruptive_inframe_deletion

Prot: ENSP00000505384.1UniProt: 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	AF: 0.00000658	AC:1	Hom:0	AN:152084	Cov:33
GnomAD2 exomes	AF: 0.00000399	AC:1	Hom:	AN:250412	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461602	Cov:
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:152084	Cov:33
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000742	AC:1	Hom:0	AN:13470	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	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 pred.	Score	Prediction
Mutation Taster	N/A	80/20	polymorphism
PhyloP100	Uncertain	5.8

Showing 2 of 2 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs748331272;

hg19: chr1-197112812;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar