1-197101685-T-C

Variant names:

• chr1-197101685-T-C
• rs1412640
• NM_018136.5:c.7566A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018136.5(ASPM):​c.7566A>G​(p.Leu2522Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,612,026 control chromosomes in the GnomAD database, including 645,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2522L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.81 (52044 hom., cov: 32)
  • Exomes 𝑓: 0.90 (593586 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.356
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-197101685-T-C is Benign according to our data. Variant chr1-197101685-T-C is described in ClinVar as Benign. ClinVar VariationId is 21602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.356 with no splicing effect.
• 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.7566A>G	p.Leu2522Leu	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5521A>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.7566A>G	p.Leu2522Leu	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5521A>G		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5521A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123089 AN: 151598 Hom.: 52003 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.834

GnomAD2 exomes AF: 0.895 AC: 223759 AN: 249892 AF XY: 0.900

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.906

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.899 AC: 1313541 AN: 1460310 Hom.: 593586 Cov.: 69 AF XY: 0.900 AC XY: 654203 AN XY: 726508

African (AFR) AF: 0.535 AC: 17862 AN: 33414

American (AMR) AF: 0.935 AC: 41653 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 23830 AN: 26092

East Asian (EAS) AF: 1.00 AC: 39646 AN: 39656

South Asian (SAS) AF: 0.899 AC: 77532 AN: 86228

European-Finnish (FIN) AF: 0.932 AC: 49441 AN: 53036

Middle Eastern (MID) AF: 0.871 AC: 5018 AN: 5758

European-Non Finnish (NFE) AF: 0.904 AC: 1004836 AN: 1111250

Other (OTH) AF: 0.891 AC: 53723 AN: 60306

GnomAD4 genome AF: 0.812 AC: 123184 AN: 151716 Hom.: 52044 Cov.: 32 AF XY: 0.815 AC XY: 60432 AN XY: 74166

African (AFR) AF: 0.547 AC: 22674 AN: 41416

American (AMR) AF: 0.884 AC: 13398 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 3167 AN: 3462

East Asian (EAS) AF: 0.999 AC: 5132 AN: 5136

South Asian (SAS) AF: 0.899 AC: 4342 AN: 4830

European-Finnish (FIN) AF: 0.928 AC: 9843 AN: 10602

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61733 AN: 67800

Other (OTH) AF: 0.836 AC: 1759 AN: 2104

Alfa AF: 0.874 Hom.: 76680

Bravo AF: 0.798

Asia WGS AF: 0.929 AC: 3228 AN: 3476

EpiCase AF: 0.906

EpiControl AF: 0.910

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.52
DANN	Benign	0.55
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1412640; hg19: chr1-197070815;