rs12025066

chr1-197143315-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018136.5(ASPM):c.937A>G(p.Ile313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,613,938 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 4 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: -0.0230

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025365055).

BP6

Variant 1-197143315-T-C is Benign according to our data. Variant chr1-197143315-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0004 (61/152320) while in subpopulation EAS AF= 0.0116 (60/5192). AF 95% confidence interval is 0.00922. There are 2 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.937A>G	p.Ile313Val	missense_variant	3/28	ENST00000367409.9
ASPM	NM_001206846.2 linkuse as main transcript	c.937A>G	p.Ile313Val	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.937A>G	p.Ile313Val	missense_variant	3/28	1	NM_018136.5	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000885

AC:

222

AN:

250924

Hom.:

AF XY:

0.000869

AC XY:

118

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0119

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000351

AC:

513

AN:

1461618

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0116

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000400

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000580

Hom.:

Bravo

AF:

0.000434

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 29, 2014	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2023	- -

ASPM-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

Cadd

Benign

1.7

Dann

Benign

0.76

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.0080

Sift

Benign

0.49

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.081

B;.

Vest4

0.034

MVP

0.048

ClinPred

0.0044

GERP RS

0.092

Varity_R

0.025

gMVP

0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over