rs587783235

Variant names:

• chr1-197122053-A-C
• rs41299587
• NM_018136.5:c.3742-10T>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.3742-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,610,884 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (88 hom.)
• Consequence: ASPM NM_018136.5 intron
• Scores: Splicing: ADA: 0.0009193
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.18
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-197122053-A-C is Benign according to our data. Variant chr1-197122053-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00645 (982/152280) while in subpopulation NFE AF = 0.0101 (684/68004). AF 95% confidence interval is 0.00943. There are 7 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.3742-10T>G		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.3742-10T>G		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.3742-10T>G		intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.3742-10T>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.1784-10T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 981 AN: 152162 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00705 AC: 1741 AN: 247014 AF XY: 0.00702

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00378

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00998

GnomAD4 exome AF: 0.00966 AC: 14094 AN: 1458604 Hom.: 88 Cov.: 32 AF XY: 0.00942 AC XY: 6834 AN XY: 725664

African (AFR) AF: 0.00153 AC: 51 AN: 33378

American (AMR) AF: 0.00614 AC: 273 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 538 AN: 26076

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86114

European-Finnish (FIN) AF: 0.00368 AC: 196 AN: 53190

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5758

European-Non Finnish (NFE) AF: 0.0112 AC: 12389 AN: 1109786

Other (OTH) AF: 0.00878 AC: 529 AN: 60248

GnomAD4 genome AF: 0.00645 AC: 982 AN: 152280 Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74466

African (AFR) AF: 0.00185 AC: 77 AN: 41568

American (AMR) AF: 0.00726 AC: 111 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 68004

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00811 Hom.: 5

Bravo AF: 0.00680

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephaly 5, primary, autosomal recessive (4)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	ASPM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.53
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -45

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

Other links and lift over

dbSNP: rs41299587; hg19: chr1-197091183;