1-197095999-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPM	NM_018136.5	c.8986C>G	p.Arg2996Gly	missense_variant, splice_region_variant	Exon 19 of 28	ENST00000367409.9	NP_060606.3
ASPM	NM_001206846.2	c.4231C>G	p.Arg1411Gly	missense_variant, splice_region_variant	Exon 18 of 27		NP_001193775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPM	ENST00000367409.9	c.8986C>G	p.Arg2996Gly	missense_variant, splice_region_variant	Exon 19 of 28	1	NM_018136.5	ENSP00000356379.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.85	T;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.058	T;D;D
Sift4G	Uncertain	0.032	D;D;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-197065129;