rs587783241

Variant summary

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

The NM_018136.5(ASPM):​c.4118_4120delATT​(p.Tyr1373del) variant causes a disruptive 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). Synonymous variant affecting the same amino acid position (i.e. Y1373Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ASPM
NM_018136.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

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]

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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=3, 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 rank MANE Protein UniProt
ASPMNM_018136.5 linkc.4118_4120delATT p.Tyr1373del disruptive_inframe_deletion Exon 18 of 28 ENST00000367409.9 NP_060606.3 Q8IZT6-1B3KWI2
ASPMNM_001206846.2 linkc.4066-8969_4066-8967delATT intron_variant Intron 17 of 26 NP_001193775.1 Q8IZT6-2B3KWI2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkc.4118_4120delATT p.Tyr1373del disruptive_inframe_deletion Exon 18 of 28 1 NM_018136.5 ENSP00000356379.4 Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
151902
Hom.:
0
Cov.:
32
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:
97
AN:
248016
Hom.:
0
AF XY:
0.000416
AC XY:
56
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.:
0
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:
50
AN:
152020
Hom.:
0
Cov.:
32
AF XY:
0.000350
AC XY:
26
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.:
0
Bravo
AF:
0.000336
EpiCase
AF:
0.000765
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Uncertain:3
May 29, 2020
New York Genome Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 11, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2Benign:1
Dec 29, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 28, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

not specified Benign:1
Oct 02, 2024
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Aug 01, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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.

Other links and lift over

dbSNP: rs587783241; hg19: chr1-197074260; API