NM_018136.5:c.*158T>C

Variant names:

• chr1-197084166-A-G
• rs41265225
• NM_018136.5:c.*158T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId is 210340.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.*158T>C		3_prime_UTR	Exon 28 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.*158T>C		3_prime_UTR	Exon 27 of 27	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.*158T>C		3_prime_UTR	Exon 28 of 28	ENSP00000356379.4	Q8IZT6-1
	ASPM	ENST00000294732.11	TSL:1	c.*158T>C		3_prime_UTR	Exon 27 of 27	ENSP00000294732.7	Q8IZT6-2
	ASPM	ENST00000367408.6	TSL:1	n.3879T>C		non_coding_transcript_exon	Exon 18 of 18

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

African (AFR) AF: 0.00179 AC: 23 AN: 12854

American (AMR) AF: 0.0117 AC: 237 AN: 20324

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 189 AN: 14614

East Asian (EAS) AF: 0.0000321 AC: 1 AN: 31112

South Asian (SAS) AF: 0.0101 AC: 461 AN: 45722

European-Finnish (FIN) AF: 0.00168 AC: 53 AN: 31516

Middle Eastern (MID) AF: 0.0158 AC: 33 AN: 2084

European-Non Finnish (NFE) AF: 0.0140 AC: 4010 AN: 285694

Other (OTH) AF: 0.0125 AC: 336 AN: 26960

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

African (AFR) AF: 0.00197 AC: 82 AN: 41592

American (AMR) AF: 0.00961 AC: 147 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 906 AN: 68002

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0121 Hom.: 3

Bravo AF: 0.00897

Asia WGS AF: 0.00290 AC: 10 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Microcephaly 5, primary, autosomal recessive (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.25
DANN	Benign	0.64
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs41265225; hg19: chr1-197053296;