1-197143675-G-C

Position:

• chr1-197143675-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018136.5(ASPM):​c.577C>G​(p.Gln193Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3155132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.577C>G	p.Gln193Glu	missense_variant	3/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.577C>G	p.Gln193Glu	missense_variant	3/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.577C>G	p.Gln193Glu	missense_variant	3/28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250370 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461592 Hom.: 0 Cov.: 36 AF XY: 0.00000688 AC XY: 5 AN XY: 727090

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.081	B;.
Vest4		0.30
MutPred		0.16		Loss of MoRF binding (P = 0.057);Loss of MoRF binding (P = 0.057);
MVP		0.53
ClinPred		0.70	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.23

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: rs199422134; hg19: chr1-197112805;