1-197086795-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.10331+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,591,854 control chromosomes in the GnomAD database, including 632,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 50011 hom., cov: 32)

Exomes 𝑓: 0.90 ( 582345 hom. )

Consequence

ASPM
NM_018136.5 splice_region, intron

Scores

Splicing: ADA: 0.00002200

Clinical Significance

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

Conservation

PhyloP100: -0.0560

Publications

17 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 (BayesDel_noAF=-0.81).

BP6

Variant 1-197086795-T-C is Benign according to our data. Variant chr1-197086795-T-C is described in ClinVar as [Benign]. Clinvar id is 157775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.10331+8A>G		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.5576+8A>G		splice_region_variant, intron_variant	Intron 26 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.10331+8A>G		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.784

AC:

119202

AN:

152018

Hom.:

49988

Cov.:

show subpopulations

Gnomad AFR

AF:

0.451

Gnomad AMI

AF:

0.955

Gnomad AMR

AF:

0.871

Gnomad ASJ

AF:

0.902

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.898

Gnomad FIN

AF:

0.929

Gnomad MID

AF:

0.888

Gnomad NFE

AF:

0.910

Gnomad OTH

AF:

0.813

GnomAD2 exomes

AF:

0.888

AC:

222168

AN:

250278

AF XY:

0.894

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.935

Gnomad ASJ exome

AF:

0.894

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.906

Gnomad OTH exome

AF:

0.900

GnomAD4 exome

AF:

0.896

AC:

1290168

AN:

1439718

Hom.:

582345

Cov.:

AF XY:

0.898

AC XY:

644244

AN XY:

717764

show subpopulations

African (AFR)

AF:

0.433

AC:

14324

AN:

33056

American (AMR)

AF:

0.929

AC:

41526

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.900

AC:

23382

AN:

25978

East Asian (EAS)

AF:

1.00

AC:

39412

AN:

39422

South Asian (SAS)

AF:

0.898

AC:

77069

AN:

85776

European-Finnish (FIN)

AF:

0.932

AC:

49533

AN:

53128

Middle Eastern (MID)

AF:

0.866

AC:

4876

AN:

5632

European-Non Finnish (NFE)

AF:

0.904

AC:

987399

AN:

1092418

Other (OTH)

AF:

0.883

AC:

52647

AN:

59624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

5642

11284

16925

22567

28209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.784

AC:

119275

AN:

152136

Hom.:

50011

Cov.:

AF XY:

0.789

AC XY:

58661

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.451

AC:

18714

AN:

41462

American (AMR)

AF:

0.872

AC:

13319

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.902

AC:

3130

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5146

AN:

5150

South Asian (SAS)

AF:

0.898

AC:

4335

AN:

4826

European-Finnish (FIN)

AF:

0.929

AC:

9857

AN:

10616

Middle Eastern (MID)

AF:

0.900

AC:

261

AN:

290

European-Non Finnish (NFE)

AF:

0.910

AC:

61920

AN:

68018

Other (OTH)

AF:

0.815

AC:

1722

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1019

2038

3058

4077

5096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.864

Hom.:

155752

Bravo

AF:

0.765

Asia WGS

AF:

0.920

AC:

3191

AN:

3470

EpiCase

AF:

0.906

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Feb 16, 2015

Eurofins Ntd Llc (ga)

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

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Aug 02, 2017

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 5, primary, autosomal recessive

Benign:3

Jul 14, 2021

Genome-Nilou Lab

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.0

(source)

DANN

Benign

0.49

PhyloP100

-0.056

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0

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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1-197086795-T-C

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