rs4915344

Positions:

• chr1-197133615-A-G
• chr1-197133615-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000367409.9(ASPM):​c.2174-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,607,116 control chromosomes in the GnomAD database, including 39,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3872 hom., cov: 32)
  • Exomes 𝑓: 0.19 (35883 hom.)
• Consequence: ASPM ENST00000367409.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.883

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-197133615-A-G is Benign according to our data. Variant chr1-197133615-A-G is described in ClinVar as [Benign]. Clinvar id is 95887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197133615-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.2174-20T>C		intron_variant		ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.2174-20T>C		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.2174-20T>C		intron_variant		1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26819 AN: 152042 Hom.: 3862 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.257 AC: 64373 AN: 250084 Hom.: 12228 AF XY: 0.249 AC XY: 33714 AN XY: 135262

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.705

Gnomad SAS exome AF: 0.281

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.192 AC: 279570 AN: 1454956 Hom.: 35883 Cov.: 31 AF XY: 0.194 AC XY: 140251 AN XY: 724216

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.684

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.176 AC: 26836 AN: 152160 Hom.: 3872 Cov.: 32 AF XY: 0.189 AC XY: 14046 AN XY: 74382

Gnomad4 AFR AF: 0.0443

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.197

Alfa AF: 0.159 Hom.: 509

Bravo AF: 0.180

Asia WGS AF: 0.486 AC: 1690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Microcephaly 5, primary, autosomal recessive Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.1
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs4915344; hg19: chr1-197102745; COSMIC: COSV54132578;