4-2875995-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001354761.2(ADD1):c.80G>T(p.Arg27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,782 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: 0.0000034 ( 0 hom. )
Consequence
ADD1
NM_001354761.2 missense
NM_001354761.2 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 7.86
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.778
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADD1 | NM_001354761.2 | c.80G>T | p.Arg27Leu | missense_variant | 2/16 | ENST00000683351.1 | NP_001341690.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADD1 | ENST00000683351.1 | c.80G>T | p.Arg27Leu | missense_variant | 2/16 | NM_001354761.2 | ENSP00000508142.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251312Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461782Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727196
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GnomAD4 genome Cov.: 32
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32
Bravo
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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 submitter | clinical testing | Ambry Genetics | Mar 20, 2023 | The c.80G>T (p.R27L) alteration is located in exon 2 (coding exon 1) of the ADD1 gene. This alteration results from a G to T substitution at nucleotide position 80, causing the arginine (R) at amino acid position 27 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;T;.;T;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.;.;.;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;N;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;T;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;.;D
Vest4
MutPred
Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);Gain of glycosylation at Y24 (P = 0.0021);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at