1-197101312-G-T

Position:

chr1-197101312-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018136.5(ASPM):c.7939C>A(p.Leu2647Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,610,322 control chromosomes in the GnomAD database, including 129,579 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 0.30 ( 8818 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120761 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.00200

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046061575).

BP6

Variant 1-197101312-G-T is Benign according to our data. Variant chr1-197101312-G-T is described in ClinVar as [Benign]. Clinvar id is 21611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101312-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.7939C>A	p.Leu2647Ile	missense_variant	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.4066-5148C>A		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.7939C>A	p.Leu2647Ile	missense_variant	18/28	1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46211

AN:

151428

Hom.:

8822

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.406

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.373

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.329

GnomAD3 exomes

AF:

0.334

AC:

83078

AN:

248402

Hom.:

15551

AF XY:

0.345

AC XY:

46352

AN XY:

134290

show subpopulations

Gnomad AFR exome

AF:

0.0888

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.164

Gnomad SAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.365

Gnomad NFE exome

AF:

0.431

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.397

AC:

579850

AN:

1458776

Hom.:

120761

Cov.:

AF XY:

0.397

AC XY:

287812

AN XY:

725780

show subpopulations

Gnomad4 AFR exome

AF:

0.0826

Gnomad4 AMR exome

AF:

0.217

Gnomad4 ASJ exome

AF:

0.393

Gnomad4 EAS exome

AF:

0.154

Gnomad4 SAS exome

AF:

0.308

Gnomad4 FIN exome

AF:

0.370

Gnomad4 NFE exome

AF:

0.433

Gnomad4 OTH exome

AF:

0.372

GnomAD4 genome

AF:

0.305

AC:

46211

AN:

151546

Hom.:

8818

Cov.:

AF XY:

0.301

AC XY:

22266

AN XY:

74044

show subpopulations

Gnomad4 AFR

AF:

0.0944

Gnomad4 AMR

AF:

0.268

Gnomad4 ASJ

AF:

0.399

Gnomad4 EAS

AF:

0.158

Gnomad4 SAS

AF:

0.292

Gnomad4 FIN

AF:

0.373

Gnomad4 NFE

AF:

0.436

Gnomad4 OTH

AF:

0.328

Alfa

AF:

0.405

Hom.:

31695

Bravo

AF:

0.286

TwinsUK

AF:

0.434

AC:

1609

ALSPAC

AF:

0.430

AC:

1656

ESP6500AA

AF:

0.104

AC:

460

ESP6500EA

AF:

0.435

AC:

3737

ExAC

AF:

0.339

AC:

41138

Asia WGS

AF:

0.202

AC:

706

AN:

3476

EpiCase

AF:

0.422

EpiControl

AF:

0.425

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	-	- -

Microcephaly 5, primary, autosomal recessive

Benign:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.8

DANN

Benign

0.92

DEOGEN2

Benign

0.032

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.75

REVEL

Benign

0.20

Sift

Benign

0.20

Sift4G

Benign

0.21

Polyphen

0.99

Vest4

0.18

ClinPred

0.0097

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.084

gMVP

0.0030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over