4-2904980-G-T
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_001354761.2(ADD1):c.1378G>T(p.Gly460Trp) variant causes a missense change. The variant allele was found at a frequency of 0.198 in 1,613,978 control chromosomes in the GnomAD database, including 35,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).
Frequency
Genomes: 𝑓 0.17 ( 2654 hom., cov: 32)
Exomes 𝑓: 0.20 ( 32571 hom. )
Consequence
ADD1
NM_001354761.2 missense
NM_001354761.2 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 5.68
Genes affected
ADD1 (HGNC:243): (adducin 1) Adducins are a family of cytoskeletal proteins encoded by three genes (alpha, beta, and gamma). Adducin acts as a heterodimer of the related alpha, beta, or gamma subunits. The protein encoded by this gene represents the alpha subunit. Alpha- and beta-adducin include a protease-resistant N-terminal region and a protease-sensitive, hydrophilic C-terminal region. Adducin binds with high affinity to Ca(2+)/calmodulin and is a substrate for protein kinases A and C. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0039125383).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADD1 | NM_001354761.2 | c.1378G>T | p.Gly460Trp | missense_variant | 10/16 | ENST00000683351.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADD1 | ENST00000683351.1 | c.1378G>T | p.Gly460Trp | missense_variant | 10/16 | NM_001354761.2 |
Frequencies
GnomAD3 genomes AF: 0.169 AC: 25648AN: 152000Hom.: 2654 Cov.: 32
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GnomAD3 exomes AF: 0.203 AC: 51062AN: 251244Hom.: 6182 AF XY: 0.201 AC XY: 27258AN XY: 135828
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GnomAD4 exome AF: 0.201 AC: 294479AN: 1461860Hom.: 32571 Cov.: 33 AF XY: 0.200 AC XY: 145139AN XY: 727232
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GnomAD4 genome AF: 0.169 AC: 25663AN: 152118Hom.: 2654 Cov.: 32 AF XY: 0.168 AC XY: 12518AN XY: 74344
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ClinVar
Significance: drug response
Submissions summary: Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
hydrochlorothiazide response - Efficacy Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy |
Hypertension, salt-sensitive essential, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Feb 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;.;T;T;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;D
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;M;M;M
MutationTaster
Benign
P;P;P
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N
REVEL
Benign
Sift
Benign
D;D;T;D;T;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D
Vest4
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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