rs149303254

Positions:

chr1-197122305-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_018136.5(ASPM):c.3599-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,613,766 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

ASPM
NM_018136.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9979

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.634

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 -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-197122305-T-C is Benign according to our data. Variant chr1-197122305-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157805.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00265 (403/152292) while in subpopulation AFR AF= 0.00928 (386/41574). AF 95% confidence interval is 0.00852. There are 1 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5 linkuse as main transcript	c.3599-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2 linkuse as main transcript	c.3599-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, 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.3599-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018136.5	ENSP00000356379	P1	Q8IZT6-1

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00926

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000612

AC:

153

AN:

250040

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.00902

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000298

AC:

435

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

152292

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00928

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2017	The c.3599-4 A>G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports c.3599-4 A>G was observed in 40/4404 (0.9%) alleles from individuals of African American background. Additionally, the 1000 Genomes Project reports it was observed in 3/448 (0.7%) alleles from individuals of African background and in 1/196 (0.5%) alleles from individuals of Italian background, indicating it may be a rare (benign) variant in these populations. Several in-silico splice prediction models predict that c.3599-4 A>G creates a cryptic acceptor site which may supplant or damage the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	ASPM: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

Microcephaly 5, primary, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

ASPM-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2019

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.77

Position offset: -1

DS_AL_spliceai

0.24

Position offset: -4

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