1-197084431-TAAAA-TAA

Variant names:

• chr1-197084431-TAA-T
• rs200839523
• NM_018136.5:c.10332-7_10332-6delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018136.5(ASPM):​c.10332-7_10332-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,395,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.003) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.10332-7_10332-6delTT		splice_region_variant, intron_variant	Intron 27 of 27	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.5577-7_5577-6delTT		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.10332-7_10332-6delTT		splice_region_variant, intron_variant	Intron 27 of 27	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.0000419 AC: 6 AN: 143190 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000700

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: 0.0000610

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00222 AC: 384 AN: 173358 AF XY: 0.00224

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000752

Gnomad EAS exome AF: 0.00243

Gnomad FIN exome AF: 0.00326

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00225 AC: 2824 AN: 1252596 Hom.: 0 AF XY: 0.00215 AC XY: 1353 AN XY: 629854

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

African (AFR) AF: 0.00356 AC: 102 AN: 28626

American (AMR) AF: 0.00286 AC: 115 AN: 40242

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 27 AN: 24086

East Asian (EAS) AF: 0.00125 AC: 46 AN: 36910

South Asian (SAS) AF: 0.00157 AC: 123 AN: 78180

European-Finnish (FIN) AF: 0.00168 AC: 74 AN: 44112

Middle Eastern (MID) AF: 0.00221 AC: 11 AN: 4988

European-Non Finnish (NFE) AF: 0.00235 AC: 2219 AN: 942436

Other (OTH) AF: 0.00202 AC: 107 AN: 53016

⚠️ 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: 0.0000419 AC: 6 AN: 143190 Hom.: 0 Cov.: 0 AF XY: 0.0000577 AC XY: 4 AN XY: 69328

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

African (AFR) AF: 0.0000259 AC: 1 AN: 38622

American (AMR) AF: 0.0000700 AC: 1 AN: 14290

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: 8748

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

European-Non Finnish (NFE) AF: 0.0000610 AC: 4 AN: 65582

Other (OTH) AF: 0.00 AC: 0 AN: 1942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00289 Hom.: 495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.062
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200839523; hg19: chr1-197053561;