chr11-47274581-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The ENST00000706887.1(MADD):c.81C>A(p.Ser27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MADD
ENST00000706887.1 missense
ENST00000706887.1 missense
Scores
2
5
11
Clinical Significance
Conservation
PhyloP100: -0.679
Genes affected
MADD (HGNC:6766): (MAP kinase activating death domain) Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mitogen-activated protein kinase (MAPK) and propagate the apoptotic signal. It is membrane-bound and expressed at a higher level in neoplastic cells than in normal cells. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27115017).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MADD | NM_001376571.1 | c.81C>A | p.Ser27Arg | missense_variant | 3/37 | ENST00000706887.1 | |
MADD | NR_164835.1 | n.283C>A | non_coding_transcript_exon_variant | 3/37 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MADD | ENST00000706887.1 | c.81C>A | p.Ser27Arg | missense_variant | 3/37 | NM_001376571.1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460020Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725942
GnomAD4 exome
AF:
AC:
1
AN:
1460020
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
725942
Gnomad4 AFR exome
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Gnomad4 ASJ exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | The c.81C>A (p.S27R) alteration is located in exon 3 (coding exon 2) of the MADD gene. This alteration results from a C to A substitution at nucleotide position 81, causing the serine (S) at amino acid position 27 to be replaced by an arginine (R). 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
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;T;T;T;T;T;T;T;D;T;T;D
Polyphen
1.0, 0.75, 1.0, 0.99
.;.;D;P;D;D;D;.;.;D;D;.
Vest4
0.59, 0.63, 0.61, 0.67, 0.67, 0.65, 0.64, 0.60, 0.68
MutPred
Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);
MVP
MPC
1.1
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