rs12677

Variant names:

• chr1-197084243-G-A
• rs12677
• ENST00000367408.6:n.3802C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-197084243-G-A
• chr1-197084243-G-C
• chr1-197084243-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.*81C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,029,454 control chromosomes in the GnomAD database, including 408,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (49995 hom., cov: 30)
  • Exomes 𝑓: 0.90 (358008 hom.)
• Consequence: ASPM NM_018136.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.02
• Publications: 12 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):

• microcephaly 5, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-197084243-G-A is Benign according to our data. Variant chr1-197084243-G-A is described in ClinVar as [Benign]. Clinvar id is 294591.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.*81C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.*81C>T		3_prime_UTR_variant	Exon 27 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.*81C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_018136.5	ENSP00000356379.4

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119167 AN: 151916 Hom.: 49972 Cov.: 30

Gnomad AFR AF: 0.452

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: 0.889

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.814

GnomAD4 exome AF: 0.900 AC: 789604 AN: 877420 Hom.: 358008 Cov.: 11 AF XY: 0.901 AC XY: 412116 AN XY: 457274

African (AFR) AF: 0.450 AC: 9607 AN: 21372

American (AMR) AF: 0.928 AC: 36770 AN: 39636

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 19843 AN: 22040

East Asian (EAS) AF: 1.00 AC: 36180 AN: 36186

South Asian (SAS) AF: 0.900 AC: 63909 AN: 71028

European-Finnish (FIN) AF: 0.932 AC: 43311 AN: 46460

Middle Eastern (MID) AF: 0.870 AC: 3863 AN: 4442

European-Non Finnish (NFE) AF: 0.907 AC: 539808 AN: 595150

Other (OTH) AF: 0.883 AC: 36313 AN: 41106

GnomAD4 genome AF: 0.784 AC: 119240 AN: 152034 Hom.: 49995 Cov.: 30 AF XY: 0.789 AC XY: 58643 AN XY: 74316

African (AFR) AF: 0.452 AC: 18718 AN: 41400

American (AMR) AF: 0.872 AC: 13314 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3133 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5156 AN: 5160

South Asian (SAS) AF: 0.899 AC: 4328 AN: 4816

European-Finnish (FIN) AF: 0.929 AC: 9842 AN: 10594

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

European-Non Finnish (NFE) AF: 0.910 AC: 61890 AN: 67998

Other (OTH) AF: 0.816 AC: 1723 AN: 2112

Alfa AF: 0.865 Hom.: 71805

Bravo AF: 0.765

Asia WGS AF: 0.919 AC: 3186 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 5, primary, autosomal recessive Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.59
PhyloP100		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs12677; hg19: chr1-197053373;