NM_018136.5:c.4066-3201A>G

Variant names:

• chr1-197108386-T-C
• rs12034362
• NM_018136.5:c.4066-3201A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018136.5(ASPM):​c.4066-3201A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 151,568 control chromosomes in the GnomAD database, including 3,847 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3847 hom., cov: 31)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.4066-3201A>G		intron_variant	Intron 17 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4065+9403A>G		intron_variant	Intron 17 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.4066-3201A>G		intron_variant	Intron 17 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26563 AN: 151450 Hom.: 3837 Cov.: 31

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.0650

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.175 AC: 26579 AN: 151568 Hom.: 3847 Cov.: 31 AF XY: 0.188 AC XY: 13921 AN XY: 74056

African (AFR) AF: 0.0400 AC: 1656 AN: 41364

American (AMR) AF: 0.335 AC: 5094 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3464

East Asian (EAS) AF: 0.695 AC: 3562 AN: 5128

South Asian (SAS) AF: 0.309 AC: 1489 AN: 4812

European-Finnish (FIN) AF: 0.250 AC: 2615 AN: 10478

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10990 AN: 67808

Other (OTH) AF: 0.198 AC: 416 AN: 2106

Alfa AF: 0.166 Hom.: 1247

Bravo AF: 0.179

Asia WGS AF: 0.483 AC: 1675 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.5
DANN	Benign	0.93
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs12034362; hg19: chr1-197077516;