NM_018136.5:c.9444+254T>A

Variant names:

• chr1-197091653-A-T
• rs955927
• NM_018136.5:c.9444+254T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018136.5(ASPM):​c.9444+254T>A variant causes a intron change. The variant allele was found at a frequency of 0.299 in 151,840 control chromosomes in the GnomAD database, including 8,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (8482 hom., cov: 31)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.75
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-197091653-A-T is Benign according to our data. Variant chr1-197091653-A-T is described in ClinVar as Benign. ClinVar VariationId is 668875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.9444+254T>A		intron_variant	Intron 22 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4689+254T>A		intron_variant	Intron 21 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.9444+254T>A		intron_variant	Intron 22 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45391 AN: 151722 Hom.: 8485 Cov.: 31

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.326

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45392 AN: 151840 Hom.: 8482 Cov.: 31 AF XY: 0.295 AC XY: 21870 AN XY: 74182

African (AFR) AF: 0.0923 AC: 3831 AN: 41498

American (AMR) AF: 0.264 AC: 4012 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1380 AN: 3462

East Asian (EAS) AF: 0.157 AC: 806 AN: 5148

South Asian (SAS) AF: 0.289 AC: 1395 AN: 4824

European-Finnish (FIN) AF: 0.363 AC: 3830 AN: 10548

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28972 AN: 67854

Other (OTH) AF: 0.325 AC: 681 AN: 2098

Alfa AF: 0.367 Hom.: 1451

Bravo AF: 0.280

Asia WGS AF: 0.198 AC: 691 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		3.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs955927; hg19: chr1-197060783;