rs143733126

chr1-197104027-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):c.5224T>C(p.Tyr1742His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,612,832 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1742Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (11 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.280

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008290589).
• BP6: Variant 1-197104027-A-G is Benign according to our data. Variant chr1-197104027-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157830.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000197 (30/152098) while in subpopulation AMR AF= 0.00197 (30/15232). AF 95% confidence interval is 0.00142. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.5224T>C	p.Tyr1742His	missense_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-7863T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.5224T>C	p.Tyr1742His	missense_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00211 AC: 527 AN: 250338 Hom.: 10 AF XY: 0.00155 AC XY: 210 AN XY: 135310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1460734 Hom.: 11 Cov.: 38 AF XY: 0.000304 AC XY: 221 AN XY: 726714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000749 Hom.: 0

Bravo AF: 0.000729

ExAC AF: 0.00156 AC: 189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2017	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. -

Microcephaly 5, primary, autosomal recessive Uncertain:1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	2.2
Dann	Benign	0.45
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.86	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	0.58	T
Polyphen		0.048	B
Vest4		0.085
MVP		0.048
ClinPred		0.038	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.051
gMVP		0.030

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: rs143733126; hg19: chr1-197073157;