rs1571964

Variant names:

• chr1-197143943-G-A
• rs1571964
• NM_018136.5:c.441+14C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-197143943-G-A
• chr1-197143943-G-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.441+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,592,502 control chromosomes in the GnomAD database, including 628,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (48502 hom., cov: 32)
  • Exomes 𝑓: 0.89 (579878 hom.)
• Consequence: ASPM NM_018136.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.198
• Publications: 11 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=-0.79).
• BP6: Variant 1-197143943-G-A is Benign according to our data. Variant chr1-197143943-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 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.441+14C>T		intron	N/A	NP_060606.3
	ASPM	NM_001206846.2		c.441+14C>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.441+14C>T		intron	N/A	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.441+14C>T		intron	N/A	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000680265.1		c.441+14C>T		intron	N/A	ENSP00000505384.1	A0A7P0Z491

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115902 AN: 151942 Hom.: 48485 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.955

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.898

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.798

GnomAD2 exomes AF: 0.880 AC: 218135 AN: 247926 AF XY: 0.888

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.931

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.982

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.905

Gnomad OTH exome AF: 0.895

GnomAD4 exome AF: 0.893 AC: 1286303 AN: 1440440 Hom.: 579878 Cov.: 32 AF XY: 0.895 AC XY: 642143 AN XY: 717692

African (AFR) AF: 0.358 AC: 11871 AN: 33186

American (AMR) AF: 0.925 AC: 41203 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23303 AN: 25916

East Asian (EAS) AF: 0.982 AC: 38736 AN: 39448

South Asian (SAS) AF: 0.898 AC: 76713 AN: 85432

European-Finnish (FIN) AF: 0.932 AC: 49504 AN: 53112

Middle Eastern (MID) AF: 0.863 AC: 4899 AN: 5674

European-Non Finnish (NFE) AF: 0.903 AC: 987805 AN: 1093494

Other (OTH) AF: 0.877 AC: 52269 AN: 59620

GnomAD4 genome AF: 0.763 AC: 115960 AN: 152062 Hom.: 48502 Cov.: 32 AF XY: 0.768 AC XY: 57133 AN XY: 74366

African (AFR) AF: 0.380 AC: 15706 AN: 41380

American (AMR) AF: 0.864 AC: 13205 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3130 AN: 3472

East Asian (EAS) AF: 0.979 AC: 5070 AN: 5178

South Asian (SAS) AF: 0.898 AC: 4337 AN: 4828

European-Finnish (FIN) AF: 0.929 AC: 9846 AN: 10604

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.910 AC: 61841 AN: 67986

Other (OTH) AF: 0.800 AC: 1692 AN: 2116

Alfa AF: 0.818 Hom.: 11314

Bravo AF: 0.741

Asia WGS AF: 0.909 AC: 3147 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.5
DANN	Benign	0.37
PhyloP100		0.20
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: rs1571964; hg19: chr1-197113073;