NM_018136.5:c.7353G>A

Variant names:

• chr1-197101898-C-T
• rs111487086
• NM_018136.5:c.7353G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018136.5(ASPM):​c.7353G>A​(p.Leu2451Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,612,794 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (18 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0510
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-197101898-C-T is Benign according to our data. Variant chr1-197101898-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.051 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00893 (1356/151824) while in subpopulation AFR AF = 0.029 (1203/41452). AF 95% confidence interval is 0.0277. There are 18 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.7353G>A	p.Leu2451Leu	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5734G>A		intron	N/A	NP_001193775.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.7353G>A	p.Leu2451Leu	synonymous	Exon 18 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4066-5734G>A		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2108-5734G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1324 AN: 151706 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00308 AC: 772 AN: 250248 AF XY: 0.00262

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000709

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00153 AC: 2228 AN: 1460970 Hom.: 18 Cov.: 42 AF XY: 0.00149 AC XY: 1081 AN XY: 726784

African (AFR) AF: 0.0293 AC: 980 AN: 33418

American (AMR) AF: 0.00226 AC: 101 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 413 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5760

European-Non Finnish (NFE) AF: 0.000359 AC: 399 AN: 1111480

Other (OTH) AF: 0.00441 AC: 266 AN: 60328

GnomAD4 genome AF: 0.00893 AC: 1356 AN: 151824 Hom.: 18 Cov.: 32 AF XY: 0.00850 AC XY: 631 AN XY: 74214

African (AFR) AF: 0.0290 AC: 1203 AN: 41452

American (AMR) AF: 0.00250 AC: 38 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000663 AC: 45 AN: 67828

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00674 Hom.: 8

Bravo AF: 0.00989

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Microcephaly 5, primary, autosomal recessive (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.44
DANN	Benign	0.56
PhyloP100		0.051
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	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: rs111487086; hg19: chr1-197071028;