rs759913912

Variant names:

• chr1-197084394-T-A
• rs759913912
• NM_018136.5:c.10364A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018136.5(ASPM):​c.10364A>T​(p.Asn3455Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• 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):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07763815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10364A>T	p.Asn3455Ile	missense_variant	Exon 28 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5609A>T	p.Asn1870Ile	missense_variant	Exon 27 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.10364A>T	p.Asn3455Ile	missense_variant	Exon 28 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 250304 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000616 AC: 9 AN: 1460698 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726670

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000201 AC: 9 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111626

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3455 of the ASPM protein (p.Asn3455Ile). This variant is present in population databases (rs759913912, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		1.4
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.93	P;.;.
Vest4		0.27
MutPred		0.29		Loss of disorder (P = 0.0724);.;.;
MVP		0.58
ClinPred		0.83	D
GERP RS		-1.8
Varity_R		0.26
gMVP		0.22
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs759913912; hg19: chr1-197053524;