NM_018136.5:c.8987+43_8987+46delTGTG

Variant names:

• chr1-197095951-TCACA-T
• rs200804798
• NM_018136.5:c.8987+43_8987+46delTGTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_018136.5(ASPM):​c.8987+43_8987+46delTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,483,714 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (6 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.904
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 1-197095951-TCACA-T is Benign according to our data. Variant chr1-197095951-TCACA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210362.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00405 (615/151896) while in subpopulation AFR AF = 0.0128 (532/41496). AF 95% confidence interval is 0.0119. There are 7 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.8987+43_8987+46delTGTG		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.4232+43_4232+46delTGTG		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.8987+43_8987+46delTGTG		intron	N/A	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4232+43_4232+46delTGTG		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2274+43_2274+46delTGTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 603 AN: 151778 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00147 AC: 342 AN: 232480 AF XY: 0.00128

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.000690 AC: 919 AN: 1331818 Hom.: 6 AF XY: 0.000654 AC XY: 434 AN XY: 663510

African (AFR) AF: 0.0128 AC: 382 AN: 29926

American (AMR) AF: 0.000523 AC: 21 AN: 40160

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 318 AN: 24224

East Asian (EAS) AF: 0.00 AC: 0 AN: 38582

South Asian (SAS) AF: 0.0000382 AC: 3 AN: 78468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4446

European-Non Finnish (NFE) AF: 0.0000813 AC: 82 AN: 1008684

Other (OTH) AF: 0.00203 AC: 113 AN: 55674

GnomAD4 genome AF: 0.00405 AC: 615 AN: 151896 Hom.: 7 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74254

African (AFR) AF: 0.0128 AC: 532 AN: 41496

American (AMR) AF: 0.00184 AC: 28 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67832

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00387 Hom.: 3

Bravo AF: 0.00440

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Dec 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200804798; hg19: chr1-197065081;