NM_018136.5:c.4065+789A>G

Variant names:

• chr1-197117000-T-C
• rs10922168
• NM_018136.5:c.4065+789A>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.4065+789A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,092 control chromosomes in the GnomAD database, including 3,873 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 (3873 hom., cov: 32)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.4065+789A>G		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.4065+789A>G		intron	N/A	NP_001193775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.4065+789A>G		intron	N/A	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4065+789A>G		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2107+789A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26855 AN: 151974 Hom.: 3864 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.177 AC: 26871 AN: 152092 Hom.: 3873 Cov.: 32 AF XY: 0.189 AC XY: 14048 AN XY: 74314

African (AFR) AF: 0.0454 AC: 1886 AN: 41564

American (AMR) AF: 0.335 AC: 5115 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3472

East Asian (EAS) AF: 0.696 AC: 3593 AN: 5166

South Asian (SAS) AF: 0.309 AC: 1492 AN: 4824

European-Finnish (FIN) AF: 0.248 AC: 2617 AN: 10566

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

European-Non Finnish (NFE) AF: 0.162 AC: 10999 AN: 67928

Other (OTH) AF: 0.195 AC: 412 AN: 2108

Alfa AF: 0.180 Hom.: 578

Bravo AF: 0.181

Asia WGS AF: 0.484 AC: 1678 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.077
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: rs10922168; hg19: chr1-197086130;