1-197084431-T-TAAAA

Variant names:

• chr1-197084431-T-TAAAA
• rs200839523
• NM_018136.5:c.10332-9_10332-6dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018136.5(ASPM):​c.10332-9_10332-6dupTTTT 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 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000095 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.439
• Publications: 0 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):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018136.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.10332-9_10332-6dupTTTT		splice_region intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.5577-9_5577-6dupTTTT		splice_region intron	N/A	NP_001193775.1	Q8IZT6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.10332-6_10332-5insTTTT		splice_region intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.5577-6_5577-5insTTTT		splice_region intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.3619-6_3619-5insTTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 143232 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000947 AC: 12 AN: 1267322 Hom.: 0 Cov.: 0 AF XY: 0.00000942 AC XY: 6 AN XY: 636976

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

African (AFR) AF: 0.0000342 AC: 1 AN: 29214

American (AMR) AF: 0.00 AC: 0 AN: 40880

Ashkenazi Jewish (ASJ) AF: 0.0000411 AC: 1 AN: 24324

East Asian (EAS) AF: 0.00 AC: 0 AN: 37462

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5040

European-Non Finnish (NFE) AF: 0.00000525 AC: 5 AN: 953186

Other (OTH) AF: 0.0000373 AC: 2 AN: 53664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 143232 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 69350

African (AFR) AF: 0.00 AC: 0 AN: 38632

American (AMR) AF: 0.00 AC: 0 AN: 14292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4518

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65588

Other (OTH) AF: 0.00 AC: 0 AN: 1944

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.44

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200839523; hg19: chr1-197053561;