1-197084431-TA-T

Variant names:

• chr1-197084431-TA-T
• rs200839523
• NM_018136.5:c.10332-6delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018136.5(ASPM):​c.10332-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.439

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-197084431-TA-T is Benign according to our data. Variant chr1-197084431-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1204775.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-197084431-TA-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-6delT		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-6delT		splice_region_variant, intron_variant	Intron 26 of 26		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.10332-6delT		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 500 AN: 143052 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00343

Gnomad ASJ AF: 0.00149

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.000885

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00180

Gnomad OTH AF: 0.00155

GnomAD2 exomes AF: 0.207 AC: 35898 AN: 173358 AF XY: 0.205

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.133 AC: 157885 AN: 1186624 Hom.: 1 Cov.: 0 AF XY: 0.135 AC XY: 80485 AN XY: 594382

Gnomad4 AFR exome AF: 0.241 AC: 6274 AN: 26024

Gnomad4 AMR exome AF: 0.252 AC: 9172 AN: 36452

Gnomad4 ASJ exome AF: 0.142 AC: 3186 AN: 22492

Gnomad4 EAS exome AF: 0.261 AC: 8148 AN: 31278

Gnomad4 SAS exome AF: 0.189 AC: 13429 AN: 70998

Gnomad4 FIN exome AF: 0.149 AC: 6036 AN: 40570

Gnomad4 NFE exome AF: 0.115 AC: 103924 AN: 904412

Gnomad4 Remaining exome AF: 0.143 AC: 7121 AN: 49694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00352 AC: 504 AN: 143108 Hom.: 2 Cov.: 0 AF XY: 0.00394 AC XY: 273 AN XY: 69298

Gnomad4 AFR AF: 0.00483 AC: 0.00483479 AN: 0.00483479

Gnomad4 AMR AF: 0.00350 AC: 0.00349993 AN: 0.00349993

Gnomad4 ASJ AF: 0.00149 AC: 0.0014881 AN: 0.0014881

Gnomad4 EAS AF: 0.00142 AC: 0.00142392 AN: 0.00142392

Gnomad4 SAS AF: 0.000889 AC: 0.000888889 AN: 0.000888889

Gnomad4 FIN AF: 0.0149 AC: 0.0149014 AN: 0.0149014

Gnomad4 NFE AF: 0.00180 AC: 0.00180103 AN: 0.00180103

Gnomad4 OTH AF: 0.00153 AC: 0.00153374 AN: 0.00153374

Alfa AF: 0.0832 Hom.: 495

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=98/2	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs200839523; hg19: chr1-197053561; COSMIC: COSV54124104;