rs41299623

Variant names:

• chr1-197104066-G-A
• rs41299623
• NM_018136.5:c.5185C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.5185C>T​(p.Arg1729Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,612,828 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1729Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (100 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.85
• Publications: 22 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

ENSG00000300054 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004125327).
• BP6: Variant 1-197104066-G-A is Benign according to our data. Variant chr1-197104066-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00827 (1257/151970) while in subpopulation AMR AF = 0.0148 (225/15214). AF 95% confidence interval is 0.0132. There are 11 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.5185C>T	p.Arg1729Trp	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-7902C>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.5185C>T	p.Arg1729Trp	missense	Exon 18 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4066-7902C>T		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2108-7902C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1257 AN: 151852 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0165

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.00955 AC: 2390 AN: 250290 AF XY: 0.0101

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.000762

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.00979 AC: 14307 AN: 1460858 Hom.: 100 Cov.: 38 AF XY: 0.0101 AC XY: 7330 AN XY: 726756

African (AFR) AF: 0.00135 AC: 45 AN: 33430

American (AMR) AF: 0.0109 AC: 485 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 497 AN: 26104

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39674

South Asian (SAS) AF: 0.0125 AC: 1074 AN: 86228

European-Finnish (FIN) AF: 0.00267 AC: 142 AN: 53166

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5764

European-Non Finnish (NFE) AF: 0.0102 AC: 11302 AN: 1111512

Other (OTH) AF: 0.0102 AC: 614 AN: 60342

GnomAD4 genome AF: 0.00827 AC: 1257 AN: 151970 Hom.: 11 Cov.: 32 AF XY: 0.00818 AC XY: 608 AN XY: 74292

African (AFR) AF: 0.00161 AC: 67 AN: 41514

American (AMR) AF: 0.0148 AC: 225 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 57 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4822

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 794 AN: 67896

Other (OTH) AF: 0.0171 AC: 36 AN: 2100

Alfa AF: 0.0100 Hom.: 48

Bravo AF: 0.00844

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00963 AC: 1169

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0145

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Microcephaly 5, primary, autosomal recessive (3)
-	-	3	not specified (3)
-	-	1	ASPM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.8
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.33
ClinPred		0.083	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.40
gMVP		0.089
Mutation Taster		=86/14	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: rs41299623; hg19: chr1-197073196; COSMIC: COSV99038474;