rs587783231

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.3391-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,582,452 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 85 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 90 hom. )

Consequence

ASPM
NM_018136.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.30

Publications

1 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=-0.58).

BP6

Variant 1-197122609-C-A is Benign according to our data. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197122609-C-A is described in CliVar as Benign. Clinvar id is 157804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.3391-14G>T		intron_variant	Intron 13 of 27	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.3391-14G>T		intron_variant	Intron 13 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.3391-14G>T		intron_variant	Intron 13 of 27	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2783

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0634

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00813

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00488

AC:

997

AN:

204240

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.0697

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000104

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00184

AC:

2628

AN:

1430318

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1082

AN XY:

709414

show subpopulations

African (AFR)

AF:

0.0672

AC:

2200

AN:

32756

American (AMR)

AF:

0.00345

AC:

141

AN:

40858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25624

East Asian (EAS)

AF:

0.00

AC:

AN:

38598

South Asian (SAS)

AF:

0.0000603

AC:

AN:

82908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51982

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000577

AC:

AN:

1092628

Other (OTH)

AF:

0.00353

AC:

209

AN:

59236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.0183

AC:

2780

AN:

152134

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1252

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0631

AC:

2619

AN:

41484

American (AMR)

AF:

0.00812

AC:

124

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67972

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00960

Hom.:

Bravo

AF:

0.0215

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 05, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Microcephaly 5, primary, autosomal recessive

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.58

CADD

Benign

5.2

(source)

DANN

Benign

0.77

PhyloP100

-2.3

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