chr1-197101391-C-G

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.7860G>C(p.Gln2620His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,608,614 control chromosomes in the GnomAD database, including 4,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2620K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 237 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3957 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.907

Publications

16 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 (MetaRNN=0.0013516843).

BP6

Variant 1-197101391-C-G is Benign according to our data. Variant chr1-197101391-C-G is described in ClinVar as [Benign]. Clinvar id is 21609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5 link	c.7860G>C	p.Gln2620His	missense_variant	Exon 18 of 28	ENST00000367409.9	NP_060606.3	Q8IZT6-1B3KWI2
ASPM	NM_001206846.2 link	c.4066-5227G>C		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.7860G>C	p.Gln2620His	missense_variant	Exon 18 of 28	1	NM_018136.5	ENSP00000356379.4		Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7385

AN:

151702

Hom.:

237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.0448

Gnomad ASJ

AF:

0.0840

Gnomad EAS

AF:

0.000776

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0732

Gnomad OTH

AF:

0.0572

GnomAD2 exomes

AF:

0.0507

AC:

12506

AN:

246592

AF XY:

0.0515

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.0317

Gnomad ASJ exome

AF:

0.0833

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0715

Gnomad OTH exome

AF:

0.0633

GnomAD4 exome

AF:

0.0682

AC:

99283

AN:

1456794

Hom.:

3957

Cov.:

AF XY:

0.0674

AC XY:

48851

AN XY:

724822

show subpopulations

African (AFR)

AF:

0.0127

AC:

425

AN:

33406

American (AMR)

AF:

0.0340

AC:

1511

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.0805

AC:

2100

AN:

26074

East Asian (EAS)

AF:

0.000101

AC:

AN:

39548

South Asian (SAS)

AF:

0.0322

AC:

2773

AN:

86178

European-Finnish (FIN)

AF:

0.0564

AC:

2831

AN:

50206

Middle Eastern (MID)

AF:

0.0413

AC:

235

AN:

5690

European-Non Finnish (NFE)

AF:

0.0770

AC:

85531

AN:

1111000

Other (OTH)

AF:

0.0643

AC:

3873

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5675

11350

17025

22700

28375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0486

AC:

7383

AN:

151820

Hom.:

237

Cov.:

AF XY:

0.0463

AC XY:

3432

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.0140

AC:

580

AN:

41492

American (AMR)

AF:

0.0447

AC:

679

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.0840

AC:

291

AN:

3464

East Asian (EAS)

AF:

0.000778

AC:

AN:

5142

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4818

European-Finnish (FIN)

AF:

0.0529

AC:

560

AN:

10594

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0732

AC:

4962

AN:

67810

Other (OTH)

AF:

0.0566

AC:

119

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

360

720

1079

1439

1799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0668

Hom.:

101

Bravo

AF:

0.0474

TwinsUK

AF:

0.0731

AC:

271

ALSPAC

AF:

0.0732

AC:

282

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0697

AC:

599

ExAC

AF:

0.0502

AC:

6084

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 31, 2014

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 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

- -

Microcephaly 5, primary, autosomal recessive

Benign:2Other:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 12, 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

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.5

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.031

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

-0.91

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

REVEL

Benign

0.084

Sift

Benign

0.14

Sift4G

Benign

0.58

Polyphen

0.064

Vest4

0.063

MutPred

0.19

Loss of ubiquitination at K2618 (P = 0.0801);

ClinPred

0.0079

GERP RS

-8.3

Varity_R

0.048

gMVP

0.010

Mutation Taster

=88/12

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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chr1-197101391-C-G

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