chr1-197143403-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.849C>T(p.Ser283Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,613,648 control chromosomes in the GnomAD database, including 637,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 48504 hom., cov: 32)

Exomes 𝑓: 0.89 ( 588703 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.223

Publications

27 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=-0.84).

BP6

Variant 1-197143403-G-A is Benign according to our data. Variant chr1-197143403-G-A is described in ClinVar as Benign. ClinVar VariationId is 95890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.223 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.849C>T	p.Ser283Ser	synonymous_variant	Exon 3 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.849C>T	p.Ser283Ser	synonymous_variant	Exon 3 of 27		NP_001193775.1	Q8IZT6-2B3KWI2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 link	c.849C>T	p.Ser283Ser	synonymous_variant	Exon 3 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.763

AC:

115899

AN:

151960

Hom.:

48487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.955

Gnomad AMR

AF:

0.863

Gnomad ASJ

AF:

0.901

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.897

Gnomad FIN

AF:

0.929

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.910

Gnomad OTH

AF:

0.798

GnomAD2 exomes

AF:

0.880

AC:

221090

AN:

251178

AF XY:

0.889

show subpopulations

Gnomad AFR exome

AF:

0.365

Gnomad AMR exome

AF:

0.930

Gnomad ASJ exome

AF:

0.893

Gnomad EAS exome

AF:

0.982

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.906

Gnomad OTH exome

AF:

0.896

GnomAD4 exome

AF:

0.893

AC:

1305661

AN:

1461570

Hom.:

588703

Cov.:

AF XY:

0.895

AC XY:

650758

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.360

AC:

12036

AN:

33468

American (AMR)

AF:

0.925

AC:

41345

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.899

AC:

23497

AN:

26128

East Asian (EAS)

AF:

0.982

AC:

38971

AN:

39686

South Asian (SAS)

AF:

0.898

AC:

77467

AN:

86252

European-Finnish (FIN)

AF:

0.932

AC:

49785

AN:

53410

Middle Eastern (MID)

AF:

0.864

AC:

4979

AN:

5766

European-Non Finnish (NFE)

AF:

0.904

AC:

1004615

AN:

1111754

Other (OTH)

AF:

0.877

AC:

52966

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

7765

15529

23294

31058

38823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21346

42692

64038

85384

106730

<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:

0.762

AC:

115957

AN:

152078

Hom.:

48504

Cov.:

AF XY:

0.768

AC XY:

57125

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.379

AC:

15717

AN:

41420

American (AMR)

AF:

0.864

AC:

13205

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.901

AC:

3128

AN:

3470

East Asian (EAS)

AF:

0.979

AC:

5073

AN:

5182

South Asian (SAS)

AF:

0.898

AC:

4337

AN:

4830

European-Finnish (FIN)

AF:

0.929

AC:

9853

AN:

10608

Middle Eastern (MID)

AF:

0.891

AC:

262

AN:

294

European-Non Finnish (NFE)

AF:

0.910

AC:

61822

AN:

67958

Other (OTH)

AF:

0.800

AC:

1689

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

990

1981

2971

3962

4952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

824

1648

2472

3296

4120

<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:

0.847

Hom.:

113369

Bravo

AF:

0.741

Asia WGS

AF:

0.909

AC:

3161

AN:

3478

EpiCase

AF:

0.905

EpiControl

AF:

0.909

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Benign:4

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely 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

- -

Jun 25, 2014

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

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.5

(source)

DANN

Benign

0.69

PhyloP100

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

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