1-197084264-G-T

Variant names:

• chr1-197084264-G-T
• rs1537318
• ENST00000367408.6:n.3781C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000367408.6(ASPM):​n.3781C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,258,744 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (4 hom.)
• Consequence: ASPM ENST00000367408.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000159 (176/1106926) while in subpopulation SAS AF = 0.00215 (168/78106). AF 95% confidence interval is 0.00188. There are 4 homozygotes in GnomAdExome4. There are 131 alleles in the male GnomAdExome4 subpopulation. Median coverage is 15. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367408.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.*60C>A		3_prime_UTR	Exon 28 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.*60C>A		3_prime_UTR	Exon 27 of 27	NP_001193775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367408.6	TSL:1	n.3781C>A		non_coding_transcript_exon	Exon 18 of 18
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.*60C>A		3_prime_UTR	Exon 28 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.*60C>A		3_prime_UTR	Exon 27 of 27	ENSP00000294732.7

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151818 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 176 AN: 1106926 Hom.: 4 Cov.: 15 AF XY: 0.000231 AC XY: 131 AN XY: 566478

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23858

East Asian (EAS) AF: 0.00 AC: 0 AN: 37676

South Asian (SAS) AF: 0.00215 AC: 168 AN: 78106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5050

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 794176

Other (OTH) AF: 0.000164 AC: 8 AN: 48698

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151818 Hom.: 0 Cov.: 31 AF XY: 0.0000810 AC XY: 6 AN XY: 74110

African (AFR) AF: 0.0000242 AC: 1 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.56
PhyloP100		1.5
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: rs1537318; hg19: chr1-197053394;