rs761447719

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_018136.5(ASPM):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ASPM
NM_018136.5 start_lost

Scores

4
5
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 122 codons. Genomic position: 197144034. Lost 0.035 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASPMNM_018136.5 linkc.2T>G p.Met1? start_lost Exon 1 of 28 ENST00000367409.9 NP_060606.3 Q8IZT6-1B3KWI2
ASPMNM_001206846.2 linkc.2T>G p.Met1? start_lost Exon 1 of 27 NP_001193775.1 Q8IZT6-2B3KWI2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASPMENST00000367409.9 linkc.2T>G p.Met1? start_lost Exon 1 of 28 1 NM_018136.5 ENSP00000356379.4 Q8IZT6-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1455042
Hom.:
0
Cov.:
31
AF XY:
0.00000414
AC XY:
3
AN XY:
723770
show subpopulations
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:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.032
T;.
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Benign
-0.51
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.23
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;.
Vest4
0.74
MutPred
0.62
Gain of methylation at M1 (P = 0.0158);Gain of methylation at M1 (P = 0.0158);
MVP
0.66
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-197115566; API