chr1-197103672-G-A

Position:

• chr1-197103672-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.5579C>T​(p.Ala1860Val) variant causes a missense change. The variant allele was found at a frequency of 0.00315 in 1,612,742 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1860A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (49 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.54

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008574486).
• BP6: Variant 1-197103672-G-A is Benign according to our data. Variant chr1-197103672-G-A is described in ClinVar as [Benign]. Clinvar id is 157836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197103672-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2155/151946) while in subpopulation AFR AF= 0.046 (1910/41484). AF 95% confidence interval is 0.0443. There are 50 homozygotes in gnomad4. There are 1032 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.5579C>T	p.Ala1860Val	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-7508C>T		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.5579C>T	p.Ala1860Val	missense_variant	18/28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2152 AN: 151828 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00645

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0205

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00501 AC: 1249 AN: 249192 Hom.: 23 AF XY: 0.00385 AC XY: 519 AN XY: 134704

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0180

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000330

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00200 AC: 2920 AN: 1460796 Hom.: 49 Cov.: 38 AF XY: 0.00181 AC XY: 1317 AN XY: 726742

Gnomad4 AFR exome AF: 0.0459

Gnomad4 AMR exome AF: 0.00296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0177

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.0142 AC: 2155 AN: 151946 Hom.: 50 Cov.: 33 AF XY: 0.0139 AC XY: 1032 AN XY: 74262

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.00644

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0204

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00346 Hom.: 15

Bravo AF: 0.0151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.00751 AC: 26 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2015	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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Microcephaly 5, primary, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.35
Sift	Benign	0.046	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.32
MVP		0.88
ClinPred		0.066	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.085

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: rs77138363; hg19: chr1-197072802;