NM_018136.5:c.10332-8_10332-6dupTTT

Variant names:

• chr1-197084431-T-TAAA
• rs200839523
• NM_018136.5:c.10332-8_10332-6dupTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_018136.5(ASPM):​c.10332-8_10332-6dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.439
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000461 (66/143286) while in subpopulation SAS AF = 0.00311 (14/4502). AF 95% confidence interval is 0.00188. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-8_10332-6dupTTT		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-8_5577-6dupTTT		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.10332-6_10332-5insTTT		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 66 AN: 143226 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000210

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.000625

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000542 AC: 94 AN: 173358 AF XY: 0.000567

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.000251

Gnomad EAS exome AF: 0.000162

Gnomad FIN exome AF: 0.000244

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000454 AC: 575 AN: 1266650 Hom.: 0 Cov.: 0 AF XY: 0.000495 AC XY: 315 AN XY: 636610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000685 AC: 2 AN: 29208

American (AMR) AF: 0.000171 AC: 7 AN: 40868

Ashkenazi Jewish (ASJ) AF: 0.000247 AC: 6 AN: 24316

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37458

South Asian (SAS) AF: 0.00195 AC: 154 AN: 78920

European-Finnish (FIN) AF: 0.000247 AC: 11 AN: 44478

Middle Eastern (MID) AF: 0.00139 AC: 7 AN: 5038

European-Non Finnish (NFE) AF: 0.000378 AC: 360 AN: 952726

Other (OTH) AF: 0.000447 AC: 24 AN: 53638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000461 AC: 66 AN: 143286 Hom.: 0 Cov.: 0 AF XY: 0.000490 AC XY: 34 AN XY: 69418

African (AFR) AF: 0.0000517 AC: 2 AN: 38714

American (AMR) AF: 0.000210 AC: 3 AN: 14304

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.00311 AC: 14 AN: 4502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8770

Middle Eastern (MID) AF: 0.00699 AC: 2 AN: 286

European-Non Finnish (NFE) AF: 0.000625 AC: 41 AN: 65578

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.000545 Hom.: 495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.44
Mutation Taster		=92/8	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs200839523; hg19: chr1-197053561;