rs797045233

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_020987.5(ANK3):​c.302A>T​(p.Asp101Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ANK3
NM_020987.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANK3. . Gene score misZ 2.7937 (greater than the threshold 3.09). Trascript score misZ 5.3471 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, Tourette syndrome, intellectual disability-hypotonia-spasticity-sleep disorder syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANK3NM_020987.5 linkuse as main transcriptc.302A>T p.Asp101Val missense_variant 3/44 ENST00000280772.7
ANK3NM_001204404.2 linkuse as main transcriptc.251A>T p.Asp84Val missense_variant 3/44
ANK3NM_001320874.2 linkuse as main transcriptc.302A>T p.Asp101Val missense_variant 3/43
ANK3NM_001204403.2 linkuse as main transcriptc.284A>T p.Asp95Val missense_variant 4/44

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANK3ENST00000280772.7 linkuse as main transcriptc.302A>T p.Asp101Val missense_variant 3/441 NM_020987.5 Q12955-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461620
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727124
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 17, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;.;.;T
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Uncertain
0.068
D
MutationAssessor
Uncertain
2.7
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.6
D;D;D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0050
D;D;D;D
Sift4G
Pathogenic
0.0
.;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.83
MutPred
0.68
Gain of MoRF binding (P = 0.0398);.;.;.;
MVP
0.88
MPC
1.9
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.63
gMVP
0.80

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: rs797045233; hg19: chr10-62038821; API