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GeneBe

1-197086839-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PM2_SupportingBP4_Moderate

The NM_018136.5(ASPM):c.10295T>A(p.Ile3432Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152178 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I3432I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ASPM
NM_018136.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.28

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
?
Very rare variant; Number of alleles below threshold, gnomad allele frequency = 0.0000197 (3/152178) while in subpopulation NFE AF= 0.0000441 (3/68030). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in gnomad. There are 1 alleles in male gnomad subpopulation. Median coverage is 32. This position pass quality control queck.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.24021372).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ASPMNM_018136.5 linkuse as main transcriptc.10295T>A p.Ile3432Asn missense_variant 27/28 ENST00000367409.9
ASPMNM_001206846.2 linkuse as main transcriptc.5540T>A p.Ile1847Asn missense_variant 26/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ASPMENST00000367409.9 linkuse as main transcriptc.10295T>A p.Ile3432Asn missense_variant 27/281 NM_018136.5 P1Q8IZT6-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250752
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135542
show subpopulations
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1459312
Hom.:
0
AF XY:
0.0000151
AC XY:
11
AN XY:
726124
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 27, 2022This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 3432 of the ASPM protein (p.Ile3432Asn). This variant is present in population databases (rs794727443, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ASPM-related conditions. ClinVar contains an entry for this variant (Variation ID: 196037). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 23, 2015- -
Microcephaly 5, primary, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.27
Cadd
Benign
22
Dann
Benign
0.97
DEOGEN2
Benign
0.23
T;.;T
Eigen
Benign
0.16
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
1.9
L;.;.
MutationTaster
Benign
0.83
N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Benign
0.074
Sift
Uncertain
0.0020
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
0.74
P;.;.
Vest4
0.52
MutPred
0.33
Gain of disorder (P = 0.0133);.;.;
MVP
0.54
ClinPred
0.89
D
GERP RS
5.8
Varity_R
0.45
gMVP
0.14

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs794727443; hg19: chr1-197055969; API