NM_018136.5:c.2419+12G>A

Variant names:

• chr1-197133338-C-T
• rs77191836
• NM_018136.5:c.2419+12G>A

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.2419+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,599,632 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (28 hom., cov: 32)
  • Exomes 𝑓: 0.020 (314 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.718
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-197133338-C-T is Benign according to our data. Variant chr1-197133338-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2725/152228) while in subpopulation NFE AF = 0.0212 (1444/67994). AF 95% confidence interval is 0.0203. There are 28 homozygotes in GnomAd4. There are 1277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.2419+12G>A		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.2419+12G>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.2419+12G>A		intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.2419+12G>A		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000680265.1		c.2419+12G>A		intron	N/A	ENSP00000505384.1	A0A7P0Z491

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2728 AN: 152110 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0162 AC: 3913 AN: 241242 AF XY: 0.0164

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0195 AC: 28253 AN: 1447404 Hom.: 314 Cov.: 31 AF XY: 0.0192 AC XY: 13833 AN XY: 718606

African (AFR) AF: 0.0170 AC: 556 AN: 32662

American (AMR) AF: 0.0112 AC: 471 AN: 42192

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 397 AN: 25518

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39540

South Asian (SAS) AF: 0.0158 AC: 1317 AN: 83416

European-Finnish (FIN) AF: 0.0120 AC: 635 AN: 53082

Middle Eastern (MID) AF: 0.0127 AC: 72 AN: 5674

European-Non Finnish (NFE) AF: 0.0214 AC: 23641 AN: 1105532

Other (OTH) AF: 0.0195 AC: 1163 AN: 59788

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152228 Hom.: 28 Cov.: 32 AF XY: 0.0172 AC XY: 1277 AN XY: 74446

African (AFR) AF: 0.0165 AC: 687 AN: 41540

American (AMR) AF: 0.0162 AC: 248 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4824

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1444 AN: 67994

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0187 Hom.: 13

Bravo AF: 0.0182

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.84
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77191836; hg19: chr1-197102468;