rs587783208

Positions:

• chr1-197088317-C-T

Variant summary

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

The ENST00000367409.9(ASPM):​c.10100G>A​(p.Ser3367Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASPM ENST00000367409.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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=0.37360874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10100G>A	p.Ser3367Asn	missense_variant	26/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5345G>A	p.Ser1782Asn	missense_variant	25/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.10100G>A	p.Ser3367Asn	missense_variant	26/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 13, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.038	D;T;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.57
MutPred		0.32		Loss of catalytic residue at S3367 (P = 0.0891);.;.;
MVP		0.64
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587783208; hg19: chr1-197057447;