rs964201

Positions:

• chr1-197101771-A-G

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.7480T>C​(p.Tyr2494His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,612,646 control chromosomes in the GnomAD database, including 798,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75442 hom., cov: 32)
  • Exomes 𝑓: 0.99 (722632 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 3.07

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 (MetaRNN=1.7361962E-6).
• BP6: Variant 1-197101771-A-G is Benign according to our data. Variant chr1-197101771-A-G is described in ClinVar as [Benign]. Clinvar id is 21599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101771-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.7480T>C	p.Tyr2494His	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4066-5607T>C		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.7480T>C	p.Tyr2494His	missense_variant	18/28	1	NM_018136.5	ENSP00000356379	P1

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151273 AN: 151780 Hom.: 75383 Cov.: 32

Gnomad AFR AF: 0.999

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.997

GnomAD3 exomes AF: 0.996 AC: 249662 AN: 250578 Hom.: 124374 AF XY: 0.996 AC XY: 134942 AN XY: 135436

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.997

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.994

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.995 AC: 1452975 AN: 1460748 Hom.: 722632 Cov.: 69 AF XY: 0.995 AC XY: 722899 AN XY: 726682

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.994

Gnomad4 OTH exome AF: 0.996

GnomAD4 genome AF: 0.997 AC: 151391 AN: 151898 Hom.: 75442 Cov.: 32 AF XY: 0.997 AC XY: 74045 AN XY: 74258

Gnomad4 AFR AF: 0.999

Gnomad4 AMR AF: 0.998

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 0.999

Gnomad4 NFE AF: 0.994

Gnomad4 OTH AF: 0.997

Alfa AF: 0.996 Hom.: 148733

Bravo AF: 0.997

TwinsUK AF: 0.995 AC: 3688

ALSPAC AF: 0.994 AC: 3830

ESP6500AA AF: 0.999 AC: 4401

ESP6500EA AF: 0.994 AC: 8545

ExAC AF: 0.996 AC: 120856

Asia WGS AF: 0.998 AC: 3472 AN: 3478

EpiCase AF: 0.995

EpiControl AF: 0.995

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 30, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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 18, 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 27, 2014	- -

Microcephaly 5, primary, autosomal recessive Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.13
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
ClinPred		0.0066	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.041

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: rs964201; hg19: chr1-197070901;