rs41308365

Variant names:

• chr1-197101577-G-A
• rs41308365
• NM_018136.5:c.7674C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-197101577-G-A
• chr1-197101577-G-T

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.7674C>T​(p.Ile2558Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,607,148 control chromosomes in the GnomAD database, including 128,815 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. I2558I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (8698 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120117 hom.)
• Consequence: ASPM NM_018136.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.360
• 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: 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=-0.62).
• BP6: Variant 1-197101577-G-A is Benign according to our data. Variant chr1-197101577-G-A is described in ClinVar as Benign. ClinVar VariationId is 21604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 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.7674C>T	p.Ile2558Ile	synonymous	Exon 18 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4066-5413C>T		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.7674C>T	p.Ile2558Ile	synonymous	Exon 18 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.4066-5413C>T		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.2108-5413C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.304 AC: 45981 AN: 151364 Hom.: 8702 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.335 AC: 83114 AN: 248176 AF XY: 0.346

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.397 AC: 577479 AN: 1455666 Hom.: 120117 Cov.: 51 AF XY: 0.396 AC XY: 286790 AN XY: 724434

African (AFR) AF: 0.0823 AC: 2749 AN: 33398

American (AMR) AF: 0.217 AC: 9646 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 10244 AN: 26078

East Asian (EAS) AF: 0.154 AC: 6096 AN: 39640

South Asian (SAS) AF: 0.308 AC: 26518 AN: 86176

European-Finnish (FIN) AF: 0.371 AC: 18822 AN: 50688

Middle Eastern (MID) AF: 0.371 AC: 2133 AN: 5748

European-Non Finnish (NFE) AF: 0.432 AC: 478921 AN: 1109244

Other (OTH) AF: 0.371 AC: 22350 AN: 60182

GnomAD4 genome AF: 0.304 AC: 45981 AN: 151482 Hom.: 8698 Cov.: 32 AF XY: 0.299 AC XY: 22132 AN XY: 73982

African (AFR) AF: 0.0939 AC: 3889 AN: 41430

American (AMR) AF: 0.267 AC: 4052 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1379 AN: 3456

East Asian (EAS) AF: 0.157 AC: 804 AN: 5126

South Asian (SAS) AF: 0.292 AC: 1406 AN: 4814

European-Finnish (FIN) AF: 0.370 AC: 3896 AN: 10522

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.434 AC: 29365 AN: 67662

Other (OTH) AF: 0.331 AC: 693 AN: 2094

Alfa AF: 0.303 Hom.: 1464

Bravo AF: 0.285

Asia WGS AF: 0.201 AC: 702 AN: 3474

EpiCase AF: 0.421

EpiControl AF: 0.424

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.2
DANN	Benign	0.66
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: rs41308365; hg19: chr1-197070707; COSMIC: COSV54126784;