rs199422173

Variant names:

• chr1-197101467-TTC-T
• rs199422173
• NM_018136.5:c.7782_7783delGA

Your query was ambiguous. Multiple possible variants found:

• chr1-197101467-TTC-T
• chr1-197101467-TTC-TTCTC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_018136.5(ASPM):​c.7782_7783delGA​(p.Lys2595SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,609,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ASPM NM_018136.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: -0.299
• Publications: 13 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-197101467-TTC-T is Pathogenic according to our data. Variant chr1-197101467-TTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.7782_7783delGA	p.Lys2595SerfsTer6	frameshift	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5305_4066-5304delGA		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.7782_7783delGA	p.Lys2595SerfsTer6	frameshift	Exon 18 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4066-5305_4066-5304delGA		intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2108-5305_2108-5304delGA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151784 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000235 AC: 58 AN: 247162 AF XY: 0.000172

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000176 AC: 256 AN: 1457322 Hom.: 0 AF XY: 0.000164 AC XY: 119 AN XY: 725108

African (AFR) AF: 0.000329 AC: 11 AN: 33406

American (AMR) AF: 0.000405 AC: 18 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26078

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39576

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86172

European-Finnish (FIN) AF: 0.000198 AC: 10 AN: 50536

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1111124

Other (OTH) AF: 0.000199 AC: 12 AN: 60224

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151902 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74266

African (AFR) AF: 0.000241 AC: 10 AN: 41510

American (AMR) AF: 0.000197 AC: 3 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67862

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000646 Hom.: 0

Bravo AF: 0.000208

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Microcephaly 5, primary, autosomal recessive (19)
3	-	-	not provided (3)
1	-	-	ASPM-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.30
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs199422173; hg19: chr1-197070597; COSMIC: COSV54124580;