rs1375813973

Variant names:

• chr1-197084412-C-A
• rs1375813973
• NM_018136.5:c.10346G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018136.5(ASPM):​c.10346G>T​(p.Trp3449Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000562 in 1,602,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10346G>T	p.Trp3449Leu	missense_variant	Exon 28 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5591G>T	p.Trp1864Leu	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.10346G>T	p.Trp3449Leu	missense_variant	Exon 28 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149206 Hom.: 0 Cov.: 31

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: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1453166 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723262

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000543 AC: 6 AN: 1105138

Other (OTH) AF: 0.0000166 AC: 1 AN: 60124

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72532

African (AFR) AF: 0.00 AC: 0 AN: 40708

American (AMR) AF: 0.00 AC: 0 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67336

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with ASPM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 3449 of the ASPM protein (p.Trp3449Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	M;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.6	D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.013	B;.;.
Vest4		0.61
MutPred		0.59		Loss of MoRF binding (P = 0.0345);.;.;
MVP		0.86
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.90
gMVP		0.45
Mutation Taster		=43/57	disease causing

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: rs1375813973; hg19: chr1-197053542;