1-197105130-GAAT-G

Position:

chr1-197105130-GAAT-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PM4_SupportingBP6BS1

The NM_018136.5(ASPM):c.4118_4120del(p.Tyr1373del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,608,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ASPM
NM_018136.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 2.31

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_018136.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 1-197105130-GAAT-G is Benign according to our data. Variant chr1-197105130-GAAT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157817.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000287 (418/1456832) while in subpopulation MID AF= 0.00296 (17/5748). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4_exome. There are 221 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.4118_4120del	p.Tyr1373del	inframe_deletion	18/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.4066-8969_4066-8967del		intron_variant			NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9 linkuse as main transcript	c.4118_4120del	p.Tyr1373del	inframe_deletion	18/28	1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000391

AC:

AN:

248016

Hom.:

AF XY:

0.000416

AC XY:

AN XY:

134562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000495

Gnomad ASJ exome

AF:

0.00460

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000666

GnomAD4 exome

AF:

0.000287

AC:

418

AN:

1456832

Hom.:

AF XY:

0.000305

AC XY:

221

AN XY:

725018

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000562

Gnomad4 ASJ exome

AF:

0.00588

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000697

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000156

Gnomad4 OTH exome

AF:

0.000598

GnomAD4 genome

AF:

0.000329

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000868

Hom.:

Bravo

AF:

0.000336

EpiCase

AF:

0.000765

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 29, 2020	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2024	Previously reported in a patient with a second ASPM variant, however clinical and segregation information were not provided on this individual (PMID: 33726816); Identified in a patient with a second ASPM variant with global developmental delay and abnormal brain imaging, who also harbored a second pair of variants in a different gene (PMID: 38374194); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33726816, 38374194) -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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