rs7551108

chr1-197129938-G-Achr1-197129938-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018136.5(ASPM):c.2606C>T(p.Thr869Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T869S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.116

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18548083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.2606C>T	p.Thr869Ile	missense_variant	8/28	ENST00000367409.9
ASPM	NM_001206846.2	c.2606C>T	p.Thr869Ile	missense_variant	8/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.2606C>T	p.Thr869Ile	missense_variant	8/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.32
MutPred		0.30		Loss of glycosylation at T869 (P = 0.0131);Loss of glycosylation at T869 (P = 0.0131);.;
MVP		0.32
ClinPred		0.83	D
GERP RS		-1.5
Varity_R		0.12
gMVP		0.37

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: rs7551108; hg19: chr1-197099068;