1-197129196-G-A

Position:

chr1-197129196-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018136.5(ASPM):c.2751C>T(p.Ala917=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,611,552 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 13 hom., cov: 32)

Exomes 𝑓: 0.018 ( 305 hom. )

Consequence

ASPM
NM_018136.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.721

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 1-197129196-G-A is Benign according to our data. Variant chr1-197129196-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-197129196-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.721 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2039/152112) while in subpopulation NFE AF= 0.0201 (1366/67958). AF 95% confidence interval is 0.0192. There are 13 homozygotes in gnomad4. There are 970 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.2751C>T	p.Ala917=	synonymous_variant	9/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.2751C>T	p.Ala917=	synonymous_variant	9/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.2751C>T	p.Ala917=	synonymous_variant	9/28	1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2041

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00346

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00912

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.0149

AC:

3753

AN:

251078

Hom.:

AF XY:

0.0156

AC XY:

2116

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.00559

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00979

Gnomad FIN exome

AF:

0.0218

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0180

AC:

26238

AN:

1459440

Hom.:

305

Cov.:

AF XY:

0.0176

AC XY:

12808

AN XY:

726100

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.00537

Gnomad4 ASJ exome

AF:

0.0309

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0198

Gnomad4 OTH exome

AF:

0.0170

GnomAD4 genome

AF:

0.0134

AC:

2039

AN:

152112

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

970

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00345

Gnomad4 AMR

AF:

0.00694

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00892

Gnomad4 FIN

AF:

0.0238

Gnomad4 NFE

AF:

0.0201

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0171

EpiControl

AF:

0.0185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2014	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Microcephaly 5, primary, autosomal recessive

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.2

DANN

Benign

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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