NM_018136.5:c.7605G>A

Variant names:

• chr1-197101646-C-T
• rs10922162
• NM_018136.5:c.7605G>A

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.7605G>A​(p.Val2535Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,611,328 control chromosomes in the GnomAD database, including 39,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V2535V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3836 hom., cov: 33)
  • Exomes 𝑓: 0.19 (35971 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.171
• Publications: 29 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-197101646-C-T is Benign according to our data. Variant chr1-197101646-C-T is described in ClinVar as Benign. ClinVar VariationId is 21603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.7605G>A	p.Val2535Val	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5482G>A		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.7605G>A	p.Val2535Val	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5482G>A		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5482G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26596 AN: 151548 Hom.: 3827 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.257 AC: 64162 AN: 249682 AF XY: 0.249

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.706

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.192 AC: 280881 AN: 1459662 Hom.: 35971 Cov.: 61 AF XY: 0.194 AC XY: 140694 AN XY: 726200

African (AFR) AF: 0.0336 AC: 1121 AN: 33410

American (AMR) AF: 0.455 AC: 20257 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4676 AN: 26076

East Asian (EAS) AF: 0.684 AC: 27116 AN: 39648

South Asian (SAS) AF: 0.277 AC: 23840 AN: 86216

European-Finnish (FIN) AF: 0.241 AC: 12689 AN: 52754

Middle Eastern (MID) AF: 0.131 AC: 755 AN: 5758

European-Non Finnish (NFE) AF: 0.160 AC: 177853 AN: 1110936

Other (OTH) AF: 0.209 AC: 12574 AN: 60298

GnomAD4 genome AF: 0.175 AC: 26609 AN: 151666 Hom.: 3836 Cov.: 33 AF XY: 0.188 AC XY: 13906 AN XY: 74110

African (AFR) AF: 0.0419 AC: 1735 AN: 41450

American (AMR) AF: 0.335 AC: 5075 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 660 AN: 3458

East Asian (EAS) AF: 0.696 AC: 3558 AN: 5114

South Asian (SAS) AF: 0.305 AC: 1470 AN: 4826

European-Finnish (FIN) AF: 0.249 AC: 2627 AN: 10550

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

European-Non Finnish (NFE) AF: 0.162 AC: 10978 AN: 67796

Other (OTH) AF: 0.196 AC: 412 AN: 2102

Alfa AF: 0.166 Hom.: 11949

Bravo AF: 0.180

Asia WGS AF: 0.478 AC: 1660 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.155

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephaly 5, primary, autosomal recessive (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.64
DANN	Benign	0.64
PhyloP100		0.17
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: rs10922162; hg19: chr1-197070776; COSMIC: COSV54139486;