1-197086839-A-T

Variant summary

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

The NM_018136.5(ASPM):c.10295T>A(p.Ile3432Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I3432I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.28

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=0.24021372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.10295T>A	p.Ile3432Asn	missense_variant	27/28	ENST00000367409.9
ASPM	NM_001206846.2	c.5540T>A	p.Ile1847Asn	missense_variant	26/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.10295T>A	p.Ile3432Asn	missense_variant	27/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250752 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135542

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459312 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726124

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 3432 of the ASPM protein (p.Ile3432Asn). This variant is present in population databases (rs794727443, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 196037). 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. -

Microcephaly 5, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;.;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.83	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.074
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.74	P;.;.
Vest4		0.52
MutPred		0.33		Gain of disorder (P = 0.0133);.;.;
MVP		0.54
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.45
gMVP		0.14

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: rs794727443; hg19: chr1-197055969;