chr1-197084166-A-G

Position:

• chr1-197084166-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018136.5(ASPM):​c.*158T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 623,186 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (58 hom.)
• Consequence: ASPM NM_018136.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.590

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-197084166-A-G is Benign according to our data. Variant chr1-197084166-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210340.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00839 (1278/152306) while in subpopulation NFE AF= 0.0133 (906/68002). AF 95% confidence interval is 0.0126. There are 14 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPM	NM_018136.5	c.*158T>C		3_prime_UTR_variant	28/28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.*158T>C		3_prime_UTR_variant	27/27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.*158T>C		3_prime_UTR_variant	28/28	1	NM_018136.5	ENSP00000356379	P1
ASPM	ENST00000294732.11	c.*158T>C		3_prime_UTR_variant	27/27	1		ENSP00000294732
ASPM	ENST00000367408.6	n.3879T>C		non_coding_transcript_exon_variant	18/18	1
ASPM	ENST00000680265.1	c.*158T>C		3_prime_UTR_variant	29/29			ENSP00000505384

Frequencies

GnomAD3 genomes AF: 0.00842 AC: 1282 AN: 152188 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0113 AC: 5343 AN: 470880 Hom.: 58 Cov.: 5 AF XY: 0.0114 AC XY: 2869 AN XY: 251538

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000321

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00839 AC: 1278 AN: 152306 Hom.: 14 Cov.: 32 AF XY: 0.00787 AC XY: 586 AN XY: 74462

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0102 Hom.: 1

Bravo AF: 0.00897

Asia WGS AF: 0.00290 AC: 10 AN: 3468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ASPM: BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Microcephaly 5, primary, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.25
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs41265225; hg19: chr1-197053296;