chr10-110112863-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016824.5(ADD3):c.282T>G(p.Ile94Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
ADD3
NM_016824.5 missense
NM_016824.5 missense
Scores
10
7
Clinical Significance
Conservation
PhyloP100: 1.58
Genes affected
ADD3 (HGNC:245): (adducin 3) Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADD3 | NM_016824.5 | c.282T>G | p.Ile94Met | missense_variant | 3/15 | ENST00000356080.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADD3 | ENST00000356080.9 | c.282T>G | p.Ile94Met | missense_variant | 3/15 | 1 | NM_016824.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251364Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135850
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727210
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74490
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2021 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the ADD3 protein (p.Ile94Met). This variant is present in population databases (rs777179853, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADD3-related conditions. 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;P;D
Vest4
MutPred
Gain of phosphorylation at Y97 (P = 0.153);Gain of phosphorylation at Y97 (P = 0.153);Gain of phosphorylation at Y97 (P = 0.153);
MVP
MPC
0.52
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at