1-197101577-G-A

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.7674C>T(p.Ile2558Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,607,148 control chromosomes in the GnomAD database, including 128,815 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. I2558I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 8698 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120117 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.360

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-197101577-G-A is Benign according to our data. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197101577-G-A is described in CliVar as Benign. Clinvar id is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7674C>T	p.Ile2558Ile	synonymous_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-5413C>T		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.7674C>T	p.Ile2558Ile	synonymous_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

45981

AN:

151364

Hom.:

8702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0941

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.290

Gnomad FIN

AF:

0.370

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.333

GnomAD2 exomes

AF:

0.335

AC:

83114

AN:

248176

AF XY:

0.346

show subpopulations

Gnomad AFR exome

AF:

0.0887

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:

0.431

Gnomad OTH exome

AF:

0.368

GnomAD4 exome

AF:

0.397

AC:

577479

AN:

1455666

Hom.:

120117

Cov.:

AF XY:

0.396

AC XY:

286790

AN XY:

724434

show subpopulations

African (AFR)

AF:

0.0823

AC:

2749

AN:

33398

American (AMR)

AF:

0.217

AC:

9646

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.393

AC:

10244

AN:

26078

East Asian (EAS)

AF:

0.154

AC:

6096

AN:

39640

South Asian (SAS)

AF:

0.308

AC:

26518

AN:

86176

European-Finnish (FIN)

AF:

0.371

AC:

18822

AN:

50688

Middle Eastern (MID)

AF:

0.371

AC:

2133

AN:

5748

European-Non Finnish (NFE)

AF:

0.432

AC:

478921

AN:

1109244

Other (OTH)

AF:

0.371

AC:

22350

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

18896

37793

56689

75586

94482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14102

28204

42306

56408

70510

<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:

45981

AN:

151482

Hom.:

8698

Cov.:

AF XY:

0.299

AC XY:

22132

AN XY:

73982

show subpopulations

African (AFR)

AF:

0.0939

AC:

3889

AN:

41430

American (AMR)

AF:

0.267

AC:

4052

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1379

AN:

3456

East Asian (EAS)

AF:

0.157

AC:

804

AN:

5126

South Asian (SAS)

AF:

0.292

AC:

1406

AN:

4814

European-Finnish (FIN)

AF:

0.370

AC:

3896

AN:

10522

Middle Eastern (MID)

AF:

0.445

AC:

130

AN:

292

European-Non Finnish (NFE)

AF:

0.434

AC:

29365

AN:

67662

Other (OTH)

AF:

0.331

AC:

693

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1493

2986

4479

5972

7465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.303

Hom.:

1464

Bravo

AF:

0.285

Asia WGS

AF:

0.201

AC:

702

AN:

3474

EpiCase

AF:

0.421

EpiControl

AF:

0.424

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 18, 2013

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. -

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

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.62

CADD

Benign

4.2

(source)

DANN

Benign

0.66

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