1-197101567-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018136.5(ASPM):c.7684A>G(p.Ser2562Gly) 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 1,606,932 control chromosomes in the GnomAD database, including 129,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8729 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120613 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.82

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 5, primary, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive primary microcephaly
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ASPM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005072117).

BP6

Variant 1-197101567-T-C is Benign according to our data. Variant chr1-197101567-T-C is described in ClinVar as Benign. ClinVar VariationId is 21605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.7684A>G	p.Ser2562Gly	missense	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5403A>G		intron	N/A	NP_001193775.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASPM	ENST00000367409.9	TSL:1 MANE Select	c.7684A>G	p.Ser2562Gly	missense	Exon 18 of 28	ENSP00000356379.4
ASPM	ENST00000294732.11	TSL:1	c.4066-5403A>G		intron	N/A	ENSP00000294732.7
ASPM	ENST00000367408.6	TSL:1	n.2108-5403A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46063

AN:

151450

Hom.:

8733

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0942

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.369

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.330

GnomAD2 exomes

AF:

0.335

AC:

83182

AN:

248174

AF XY:

0.346

show subpopulations

Gnomad AFR exome

AF:

0.0888

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.367

Gnomad NFE exome

AF:

0.432

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.397

AC:

578458

AN:

1455362

Hom.:

120613

Cov.:

AF XY:

0.397

AC XY:

287166

AN XY:

724186

show subpopulations

African (AFR)

AF:

0.0824

AC:

2753

AN:

33408

American (AMR)

AF:

0.217

AC:

9652

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.393

AC:

10246

AN:

26078

East Asian (EAS)

AF:

0.154

AC:

6096

AN:

39648

South Asian (SAS)

AF:

0.308

AC:

26510

AN:

86154

European-Finnish (FIN)

AF:

0.372

AC:

18786

AN:

50550

Middle Eastern (MID)

AF:

0.371

AC:

2133

AN:

5754

European-Non Finnish (NFE)

AF:

0.433

AC:

479913

AN:

1109080

Other (OTH)

AF:

0.372

AC:

22369

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

18598

37196

55794

74392

92990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14118

28236

42354

56472

70590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.304

AC:

46063

AN:

151570

Hom.:

8729

Cov.:

AF XY:

0.299

AC XY:

22162

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.0940

AC:

3896

AN:

41464

American (AMR)

AF:

0.267

AC:

4058

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1380

AN:

3462

East Asian (EAS)

AF:

0.157

AC:

807

AN:

5132

South Asian (SAS)

AF:

0.292

AC:

1408

AN:

4820

European-Finnish (FIN)

AF:

0.369

AC:

3891

AN:

10534

Middle Eastern (MID)

AF:

0.445

AC:

130

AN:

292

European-Non Finnish (NFE)

AF:

0.435

AC:

29437

AN:

67684

Other (OTH)

AF:

0.328

AC:

689

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1455

2911

4366

5822

7277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.384

Hom.:

40481

Bravo

AF:

0.286

TwinsUK

AF:

0.433

AC:

1604

ALSPAC

AF:

0.428

AC:

1651

ESP6500AA

AF:

0.104

AC:

456

ESP6500EA

AF:

0.433

AC:

3718

ExAC

AF:

0.340

AC:

41233

Asia WGS

AF:

0.201

AC:

702

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Microcephaly 5, primary, autosomal recessive

Benign:3Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

PhyloP100

1.8

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.36

Sift

Uncertain

0.021

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.52

ClinPred

0.065

GERP RS

5.2

Varity_R

0.14

gMVP

0.060

Mutation Taster

=75/25

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over