rs587783291

Variant names:

• chr1-197091899-A-C
• rs140150599
• NM_018136.5:c.9444+8T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018136.5(ASPM):​c.9444+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,609,224 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003181
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.84
• 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):

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-197091899-A-C is Benign according to our data. Variant chr1-197091899-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00256 (389/152162) while in subpopulation AFR AF = 0.00903 (375/41544). AF 95% confidence interval is 0.00827. There are 3 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.9444+8T>G		splice_region intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.4689+8T>G		splice_region intron	N/A	NP_001193775.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.9444+8T>G		splice_region intron	N/A	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4689+8T>G		splice_region intron	N/A	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2731+8T>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152044 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00903

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000635 AC: 159 AN: 250230 AF XY: 0.000503

Gnomad AFR exome AF: 0.00870

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000258 AC: 376 AN: 1457062 Hom.: 3 Cov.: 31 AF XY: 0.000229 AC XY: 166 AN XY: 724890

African (AFR) AF: 0.00907 AC: 302 AN: 33296

American (AMR) AF: 0.000291 AC: 13 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.000232 AC: 1 AN: 4308

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1109952

Other (OTH) AF: 0.000500 AC: 30 AN: 60034

GnomAD4 genome AF: 0.00256 AC: 389 AN: 152162 Hom.: 3 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74398

African (AFR) AF: 0.00903 AC: 375 AN: 41544

American (AMR) AF: 0.000722 AC: 11 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Microcephaly 5, primary, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.72
DANN	Benign	0.57
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs140150599; hg19: chr1-197061029;