rs199422173

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018136.5(ASPM):​c.7782_7783del​(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:18 O:1
• Conservation: PhyloP100: -0.299

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-197101467-TTC-T is Pathogenic according to our data. Variant chr1-197101467-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 21606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101467-TTC-T is described in Lovd as [Pathogenic]. Variant chr1-197101467-TTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.7782_7783del	p.Lys2595SerfsTer6	frameshift_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-5305_4066-5304del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.7782_7783del	p.Lys2595SerfsTer6	frameshift_variant	18/28	1	NM_018136.5	P1

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

GnomAD3 exomes AF: 0.000235 AC: 58 AN: 247162 Hom.: 0 AF XY: 0.000172 AC XY: 23 AN XY: 133812

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 SAS exome AF: 0.0000982

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

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000405

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.000199

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

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000646 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Pathogenic:12 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Oct 01, 2021	This variant was previously reported in individuals affected with autosomal recessive primary microcephaly [PMID: 19028728, 23611254, 29644084, 31589614]. Loss-of-function variants in the ASPM gene are known to be pathogenic [PMID: 19028728, 23611254] -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly 5, primary (MIM#608716). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least fifteen families with primary microcephaly and classified as pathogenic by diagnosistic laboratories in ClinVar (PMID: 29243349). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 03, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 strong -
Pathogenic, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 02, 2019	A Homozygous two base pair deletion in exon 18 of the ASPM gene that results in a frameshift and premature truncation of the protein 6 amino acids downstream to codon 2595 was detected. The observed variant c.7782_7783del (p.Lys2595SerfsTer6) has not been reported in the 1000 genomes database and has a minor allele frequency of 0.03% in the ExAC database. The in silico prediction of the variant is damaging by MutationTaster2. The reference region is conserved across mammals. -
Pathogenic, no assertion criteria provided	clinical testing	Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles	Jan 01, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Lys2595Serfs*6) in the ASPM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPM are known to be pathogenic (PMID: 19028728, 23611254). This variant is present in population databases (rs199422173, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive primary microcephaly (MCPH) (PMID: 19028728, 23611254, 29644084). ClinVar contains an entry for this variant (Variation ID: 21606). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19770472, 26548919, 29644084, 31853109, 26691732, 23611254, 19028728, 32677750, 31589614, 34426522, 34402213) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2022

The c.7782_7783delGA (p.K2595Sfs*6) alteration, located in exon 18 (coding exon 18) of the ASPM gene, consists of a deletion of 2 nucleotides from position 7782 to 7783, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Reported in the homozygous state or in trans with a second pathogenic ASPM variant in multiple patients with autosomal recessive primary microcephaly (MCPH)(Nicholas, 2009; Passemard, 2009; Tan, 2014; Kraemer, 2016; Letard, 2017; Okamoto, 2018; Ahmed, 2019; Qi, 2020; Rasool, 2020; Duerinckx, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

Microcephaly 1, primary, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

-

- -

ASPM-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

The ASPM c.7782_7783delGA variant is predicted to result in a frameshift and premature protein termination (p.Lys2595Serfs*6). This variant has been reported, both in the homozygous and compound heterozygous states with a second truncating variant, in several patients affected with primary autosomal recessive microcephaly (Rasool et al. 2020. PubMed ID: 32677750; Nicholas et al. 2009. PubMed ID: 19028728; Tan et al. 2014. PubMed ID: 23611254; Passemard et al. 2016. PubMed ID: 26691732). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in ASPM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs199422173; hg19: chr1-197070597;