rs2878749

Variant names:

• chr1-197104802-T-C
• rs2878749
• NM_018136.5:c.4449A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018136.5(ASPM):​c.4449A>G​(p.Lys1483Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,577,952 control chromosomes in the GnomAD database, including 127,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8827 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118924 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.911
• Publications: 18 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):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ENSG00000300054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-197104802-T-C is Benign according to our data. Variant chr1-197104802-T-C is described in ClinVar as Benign. ClinVar VariationId is 21586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.4449A>G	p.Lys1483Lys	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-8638A>G		intron	N/A	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.4449A>G	p.Lys1483Lys	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-8638A>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-8638A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46275 AN: 151670 Hom.: 8831 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.343 AC: 76809 AN: 224194 AF XY: 0.353

Gnomad AFR exome AF: 0.0899

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.168

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.399 AC: 569494 AN: 1426164 Hom.: 118924 Cov.: 36 AF XY: 0.398 AC XY: 281737 AN XY: 707482

African (AFR) AF: 0.0820 AC: 2579 AN: 31450

American (AMR) AF: 0.224 AC: 8451 AN: 37752

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 9718 AN: 24664

East Asian (EAS) AF: 0.154 AC: 6047 AN: 39328

South Asian (SAS) AF: 0.308 AC: 24531 AN: 79636

European-Finnish (FIN) AF: 0.371 AC: 19190 AN: 51760

Middle Eastern (MID) AF: 0.373 AC: 2076 AN: 5570

European-Non Finnish (NFE) AF: 0.433 AC: 474947 AN: 1097200

Other (OTH) AF: 0.373 AC: 21955 AN: 58804

GnomAD4 genome AF: 0.305 AC: 46275 AN: 151788 Hom.: 8827 Cov.: 32 AF XY: 0.300 AC XY: 22273 AN XY: 74152

African (AFR) AF: 0.0944 AC: 3916 AN: 41478

American (AMR) AF: 0.268 AC: 4066 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1378 AN: 3466

East Asian (EAS) AF: 0.158 AC: 814 AN: 5158

South Asian (SAS) AF: 0.292 AC: 1409 AN: 4824

European-Finnish (FIN) AF: 0.372 AC: 3911 AN: 10526

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29582 AN: 67834

Other (OTH) AF: 0.330 AC: 696 AN: 2108

Alfa AF: 0.402 Hom.: 17388

Bravo AF: 0.286

Asia WGS AF: 0.201 AC: 702 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Microcephaly 5, primary, autosomal recessive (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.54
DANN	Benign	0.55
PhyloP100		-0.91
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: rs2878749; hg19: chr1-197073932; COSMIC: COSV54127151;