1-197095999-G-C

Variant names:

• chr1-197095999-G-C
• rs772813676
• NM_018136.5:c.8986C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018136.5(ASPM):​c.8986C>G​(p.Arg2996Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2996W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASPM NM_018136.5 missense, splice_region
• Scores: Splicing: ADA: 0.001195
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	NM_018136.5	MANE Select	c.8986C>G	p.Arg2996Gly	missense splice_region	Exon 19 of 28	NP_060606.3
	ASPM	NM_001206846.2		c.4231C>G	p.Arg1411Gly	missense splice_region	Exon 18 of 27	NP_001193775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPM	ENST00000367409.9	TSL:1 MANE Select	c.8986C>G	p.Arg2996Gly	missense splice_region	Exon 19 of 28	ENSP00000356379.4
	ASPM	ENST00000294732.11	TSL:1	c.4231C>G	p.Arg1411Gly	missense splice_region	Exon 18 of 27	ENSP00000294732.7
	ASPM	ENST00000367408.6	TSL:1	n.2273C>G		splice_region non_coding_transcript_exon	Exon 9 of 18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452894 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723154

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105094

Other (OTH) AF: 0.00 AC: 0 AN: 59990

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.12
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.49
Sift	Benign	0.058	T
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.53		Loss of MoRF binding (P = 0.0466)
MVP		0.95
ClinPred		0.93	D
GERP RS		0.28
Varity_R		0.13
gMVP		0.042
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772813676; hg19: chr1-197065129;