rs587783213

Variant names:

• chr1-197086795-T-C
• rs10754213
• NM_018136.5:c.10331+8A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-197086795-T-C
• chr1-197086795-T-A
• chr1-197086795-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018136.5(ASPM):​c.10331+8A>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 0.885 in 1,591,854 control chromosomes in the GnomAD database, including 632,356 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50011 hom., cov: 32)
  • Exomes 𝑓: 0.90 (582345 hom.)
• Consequence: ASPM NM_018136.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002200
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0560
• Publications: 17 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=-0.81).
• BP6: Variant 1-197086795-T-C is Benign according to our data. Variant chr1-197086795-T-C is described in ClinVar as Benign. ClinVar VariationId is 157775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.10331+8A>G		splice_region intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.5576+8A>G		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.10331+8A>G		splice_region intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.5576+8A>G		splice_region intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.3618+8A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119202 AN: 152018 Hom.: 49988 Cov.: 32

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.888

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.813

GnomAD2 exomes AF: 0.888 AC: 222168 AN: 250278 AF XY: 0.894

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.935

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.896 AC: 1290168 AN: 1439718 Hom.: 582345 Cov.: 30 AF XY: 0.898 AC XY: 644244 AN XY: 717764

African (AFR) AF: 0.433 AC: 14324 AN: 33056

American (AMR) AF: 0.929 AC: 41526 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23382 AN: 25978

East Asian (EAS) AF: 1.00 AC: 39412 AN: 39422

South Asian (SAS) AF: 0.898 AC: 77069 AN: 85776

European-Finnish (FIN) AF: 0.932 AC: 49533 AN: 53128

Middle Eastern (MID) AF: 0.866 AC: 4876 AN: 5632

European-Non Finnish (NFE) AF: 0.904 AC: 987399 AN: 1092418

Other (OTH) AF: 0.883 AC: 52647 AN: 59624

GnomAD4 genome AF: 0.784 AC: 119275 AN: 152136 Hom.: 50011 Cov.: 32 AF XY: 0.789 AC XY: 58661 AN XY: 74372

African (AFR) AF: 0.451 AC: 18714 AN: 41462

American (AMR) AF: 0.872 AC: 13319 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3130 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5146 AN: 5150

South Asian (SAS) AF: 0.898 AC: 4335 AN: 4826

European-Finnish (FIN) AF: 0.929 AC: 9857 AN: 10616

Middle Eastern (MID) AF: 0.900 AC: 261 AN: 290

European-Non Finnish (NFE) AF: 0.910 AC: 61920 AN: 68018

Other (OTH) AF: 0.815 AC: 1722 AN: 2112

Alfa AF: 0.864 Hom.: 155752

Bravo AF: 0.765

Asia WGS AF: 0.920 AC: 3191 AN: 3470

EpiCase AF: 0.906

EpiControl AF: 0.910

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Microcephaly 5, primary, autosomal recessive (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.49
PhyloP100		-0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs10754213; hg19: chr1-197055925;