NM_020987.5:c.1375C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020987.5(ANK3):​c.1375C>A​(p.Pro459Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,848 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P459S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

10
7
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.98

Publications

2 publications found
Variant links:
Genes affected
ANK3 (HGNC:494): (ankyrin 3) Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]
ANK3 Gene-Disease associations (from GenCC):
  • intellectual disability-hypotonia-spasticity-sleep disorder syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
  • intellectual disability
    Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
  • Tourette syndrome
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANK3NM_020987.5 linkc.1375C>A p.Pro459Thr missense_variant Exon 12 of 44 ENST00000280772.7 NP_066267.2 Q12955-3
ANK3NM_001204404.2 linkc.1324C>A p.Pro442Thr missense_variant Exon 12 of 44 NP_001191333.1 Q12955-4
ANK3NM_001320874.2 linkc.1375C>A p.Pro459Thr missense_variant Exon 12 of 43 NP_001307803.1
ANK3NM_001204403.2 linkc.1357C>A p.Pro453Thr missense_variant Exon 13 of 44 NP_001191332.1 Q12955-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANK3ENST00000280772.7 linkc.1375C>A p.Pro459Thr missense_variant Exon 12 of 44 1 NM_020987.5 ENSP00000280772.1 Q12955-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000400
AC:
1
AN:
250222
AF XY:
0.00000739
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459848
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
726306
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33412
American (AMR)
AF:
0.00
AC:
0
AN:
44642
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26082
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39612
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86020
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53372
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1110664
Other (OTH)
AF:
0.00
AC:
0
AN:
60284
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.447
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000596

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
1.8
L;.;.
PhyloP100
10
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.011
D;D;D
Sift4G
Uncertain
0.033
.;D;D
Polyphen
1.0
D;.;.
Vest4
0.89
MutPred
0.46
Gain of catalytic residue at P459 (P = 0.0028);.;.;
MVP
0.83
MPC
1.6
ClinPred
0.97
D
GERP RS
5.2
Varity_R
0.50
gMVP
0.86
Mutation Taster
=67/33
polymorphism

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

Other links and lift over

dbSNP: rs749878219; hg19: chr10-61962777; API