rs4915344

Variant names:

• chr1-197133615-A-G
• rs4915344
• NM_018136.5:c.2174-20T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-197133615-A-G
• chr1-197133615-A-T

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.2174-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,607,116 control chromosomes in the GnomAD database, including 39,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3872 hom., cov: 32)
  • Exomes 𝑓: 0.19 (35883 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.883
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-197133615-A-G is Benign according to our data. Variant chr1-197133615-A-G is described in ClinVar as Benign. ClinVar VariationId is 95887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 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.2174-20T>C		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.2174-20T>C		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.2174-20T>C		intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.2174-20T>C		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000680265.1		c.2174-20T>C		intron	N/A	ENSP00000505384.1	A0A7P0Z491

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26819 AN: 152042 Hom.: 3862 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.257 AC: 64373 AN: 250084 AF XY: 0.249

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.705

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.192 AC: 279570 AN: 1454956 Hom.: 35883 Cov.: 31 AF XY: 0.194 AC XY: 140251 AN XY: 724216

African (AFR) AF: 0.0364 AC: 1214 AN: 33390

American (AMR) AF: 0.454 AC: 20277 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4666 AN: 26078

East Asian (EAS) AF: 0.684 AC: 27099 AN: 39624

South Asian (SAS) AF: 0.281 AC: 24087 AN: 85818

European-Finnish (FIN) AF: 0.241 AC: 12843 AN: 53228

Middle Eastern (MID) AF: 0.131 AC: 749 AN: 5700

European-Non Finnish (NFE) AF: 0.159 AC: 176103 AN: 1106330

Other (OTH) AF: 0.208 AC: 12532 AN: 60160

GnomAD4 genome AF: 0.176 AC: 26836 AN: 152160 Hom.: 3872 Cov.: 32 AF XY: 0.189 AC XY: 14046 AN XY: 74382

African (AFR) AF: 0.0443 AC: 1839 AN: 41558

American (AMR) AF: 0.334 AC: 5105 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3466

East Asian (EAS) AF: 0.695 AC: 3592 AN: 5168

South Asian (SAS) AF: 0.310 AC: 1493 AN: 4822

European-Finnish (FIN) AF: 0.249 AC: 2628 AN: 10574

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11007 AN: 67986

Other (OTH) AF: 0.197 AC: 416 AN: 2116

Alfa AF: 0.160 Hom.: 895

Bravo AF: 0.180

Asia WGS AF: 0.486 AC: 1690 AN: 3478

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 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.1
DANN	Benign	0.84
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs4915344; hg19: chr1-197102745; COSMIC: COSV54132578;