chr1-197101898-C-A

Position:

• chr1-197101898-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018136.5(ASPM):​c.7353G>T​(p.Leu2451Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L2451L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASPM NM_018136.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21826684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPM	NM_018136.5	c.7353G>T	p.Leu2451Phe	missense_variant	18/28	ENST00000367409.9
ASPM	NM_001206846.2	c.4066-5734G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPM	ENST00000367409.9	c.7353G>T	p.Leu2451Phe	missense_variant	18/28	1	NM_018136.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250248 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460970 Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1 AN XY: 726784

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.055	T
Sift4G	Benign	0.065	T
Polyphen		0.35	B
Vest4		0.24
MutPred		0.42		Gain of methylation at K2448 (P = 0.0712);
MVP		0.79
ClinPred		0.37	T
GERP RS		-1.5
Varity_R		0.036
gMVP		0.011

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: rs111487086; hg19: chr1-197071028;