chr1-197112552-G-A

Variant names:

• chr1-197112552-G-A
• rs12085377
• NM_018136.5:c.4065+5237C>T

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+5237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 151,982 control chromosomes in the GnomAD database, including 3,849 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 (3849 hom., cov: 32)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.579
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.4065+5237C>T		intron_variant	Intron 17 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4065+5237C>T		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.4065+5237C>T		intron_variant	Intron 17 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26770 AN: 151864 Hom.: 3840 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.249

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: 0.176 AC: 26784 AN: 151982 Hom.: 3849 Cov.: 32 AF XY: 0.189 AC XY: 14006 AN XY: 74266

African (AFR) AF: 0.0443 AC: 1840 AN: 41492

American (AMR) AF: 0.335 AC: 5097 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 663 AN: 3468

East Asian (EAS) AF: 0.694 AC: 3576 AN: 5150

South Asian (SAS) AF: 0.308 AC: 1482 AN: 4816

European-Finnish (FIN) AF: 0.249 AC: 2624 AN: 10554

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

European-Non Finnish (NFE) AF: 0.162 AC: 10995 AN: 67946

Other (OTH) AF: 0.195 AC: 413 AN: 2114

Alfa AF: 0.154 Hom.: 283

Bravo AF: 0.180

Asia WGS AF: 0.481 AC: 1671 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.9
DANN	Benign	0.32
PhyloP100		-0.58
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: rs12085377; hg19: chr1-197081682; COSMIC: COSV54127509;