1-197104168-G-C

Position:

• chr1-197104168-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.5083C>G​(p.Arg1695Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80

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 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=0.40329856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.5083C>G	p.Arg1695Gly	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-8004C>G		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.5083C>G	p.Arg1695Gly	missense_variant	18/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249620 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134940

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 SAS 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: 6.85e-7 AC: 1 AN: 1460678 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 726618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.65	P
Vest4		0.44
MutPred		0.57		Loss of MoRF binding (P = 0.0999);
MVP		0.87
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs80238010; hg19: chr1-197073298;