1-197101685-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018136.5(ASPM):c.7566A>G(p.Leu2522Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,612,026 control chromosomes in the GnomAD database, including 645,630 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. L2522L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.81 ( 52044 hom., cov: 32)

Exomes 𝑓: 0.90 ( 593586 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: -0.356

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 1-197101685-T-C is Benign according to our data. Variant chr1-197101685-T-C is described in ClinVar as Benign. ClinVar VariationId is 21602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.356 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7566A>G	p.Leu2522Leu	synonymous_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-5521A>G		intron_variant	Intron 17 of 26		NP_001193775.1	Q8IZT6-2B3KWI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.7566A>G	p.Leu2522Leu	synonymous_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123089

AN:

151598

Hom.:

52003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.955

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.915

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.898

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.911

Gnomad OTH

AF:

0.834

GnomAD2 exomes

AF:

0.895

AC:

223759

AN:

249892

AF XY:

0.900

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.939

Gnomad ASJ exome

AF:

0.907

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.906

Gnomad OTH exome

AF:

0.904

GnomAD4 exome

AF:

0.899

AC:

1313541

AN:

1460310

Hom.:

593586

Cov.:

AF XY:

0.900

AC XY:

654203

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.535

AC:

17862

AN:

33414

American (AMR)

AF:

0.935

AC:

41653

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.913

AC:

23830

AN:

26092

East Asian (EAS)

AF:

1.00

AC:

39646

AN:

39656

South Asian (SAS)

AF:

0.899

AC:

77532

AN:

86228

European-Finnish (FIN)

AF:

0.932

AC:

49441

AN:

53036

Middle Eastern (MID)

AF:

0.871

AC:

5018

AN:

5758

European-Non Finnish (NFE)

AF:

0.904

AC:

1004836

AN:

1111250

Other (OTH)

AF:

0.891

AC:

53723

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7882

15763

23645

31526

39408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21402

42804

64206

85608

107010

<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:

0.812

AC:

123184

AN:

151716

Hom.:

52044

Cov.:

AF XY:

0.815

AC XY:

60432

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.547

AC:

22674

AN:

41416

American (AMR)

AF:

0.884

AC:

13398

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.915

AC:

3167

AN:

3462

East Asian (EAS)

AF:

0.999

AC:

5132

AN:

5136

South Asian (SAS)

AF:

0.899

AC:

4342

AN:

4830

European-Finnish (FIN)

AF:

0.928

AC:

9843

AN:

10602

Middle Eastern (MID)

AF:

0.901

AC:

265

AN:

294

European-Non Finnish (NFE)

AF:

0.911

AC:

61733

AN:

67800

Other (OTH)

AF:

0.836

AC:

1759

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

984

1968

2953

3937

4921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<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:

0.874

Hom.:

76680

Bravo

AF:

0.798

Asia WGS

AF:

0.929

AC:

3228

AN:

3476

EpiCase

AF:

0.906

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Feb 27, 2014

Eurofins Ntd Llc (ga)

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

- -

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

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Benign:4Other:1

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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.52

(source)

DANN

Benign

0.55

PhyloP100

-0.36

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over