chr1-197086795-T-C

Position:

• chr1-197086795-T-C

Variant summary

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

The NM_018136.5(ASPM):​c.10331+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,591,854 control chromosomes in the GnomAD database, including 632,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50011 hom., cov: 32)
  • Exomes 𝑓: 0.90 (582345 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002200
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0560

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=-0.81).
• BP6: Variant 1-197086795-T-C is Benign according to our data. Variant chr1-197086795-T-C is described in ClinVar as [Benign]. Clinvar id is 157775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197086795-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.10331+8A>G		splice_region_variant, intron_variant		ENST00000367409.9
ASPM	NM_001206846.2	c.5576+8A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.10331+8A>G		splice_region_variant, intron_variant		1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119202 AN: 152018 Hom.: 49988 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.888

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.813

GnomAD3 exomes AF: 0.888 AC: 222168 AN: 250278 Hom.: 100509 AF XY: 0.894 AC XY: 121046 AN XY: 135378

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.935

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.899

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.896 AC: 1290168 AN: 1439718 Hom.: 582345 Cov.: 30 AF XY: 0.898 AC XY: 644244 AN XY: 717764

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.929

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.904

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.784 AC: 119275 AN: 152136 Hom.: 50011 Cov.: 32 AF XY: 0.789 AC XY: 58661 AN XY: 74372

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.902

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.898

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.815

Alfa AF: 0.891 Hom.: 117237

Bravo AF: 0.765

Asia WGS AF: 0.920 AC: 3191 AN: 3470

EpiCase AF: 0.906

EpiControl AF: 0.910

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephaly 5, primary, autosomal recessive Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs10754213; hg19: chr1-197055925;