NM_018136.5:c.8449G>T

Variant names:

• chr1-197100802-C-A
• rs117963393
• NM_018136.5:c.8449G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):​c.8449G>T​(p.Ala2817Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,612,538 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2817D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (12 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.837
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038597882).
• BP6: Variant 1-197100802-C-A is Benign according to our data. Variant chr1-197100802-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157892.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000863 (131/151788) while in subpopulation EAS AF = 0.0236 (121/5130). AF 95% confidence interval is 0.0202. There are 3 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.8449G>T	p.Ala2817Ser	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-4638G>T		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.8449G>T	p.Ala2817Ser	missense	Exon 18 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4066-4638G>T		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2108-4638G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000877 AC: 133 AN: 151670 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00194 AC: 486 AN: 250082 AF XY: 0.00188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0254

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000495 AC: 723 AN: 1460750 Hom.: 12 Cov.: 31 AF XY: 0.000489 AC XY: 355 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.0000224 AC: 1 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0159 AC: 631 AN: 39674

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111326

Other (OTH) AF: 0.000663 AC: 40 AN: 60332

GnomAD4 genome AF: 0.000863 AC: 131 AN: 151788 Hom.: 3 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74174

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.000197 AC: 3 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0236 AC: 121 AN: 5130

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67802

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000410 Hom.: 0

Bravo AF: 0.00136

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Microcephaly 5, primary, autosomal recessive (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.84
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Benign	0.039	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.32
MVP		0.66
ClinPred		0.063	T
GERP RS		1.7
Varity_R		0.049
gMVP		0.0048
Mutation Taster		=94/6	polymorphism

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: rs117963393; hg19: chr1-197069932; COSMIC: COSV54130346;