11-47274969-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The ENST00000706887.1(MADD):c.469C>T(p.Pro157Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,614,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00066 ( 2 hom. )
Consequence
MADD
ENST00000706887.1 missense
ENST00000706887.1 missense
Scores
3
6
9
Clinical Significance
Conservation
PhyloP100: 5.62
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 Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.045625865).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000655 (958/1461812) while in subpopulation NFE AF= 0.000769 (855/1112000). AF 95% confidence interval is 0.000725. There are 2 homozygotes in gnomad4_exome. There are 468 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MADD | NM_001376571.1 | c.469C>T | p.Pro157Ser | missense_variant | 3/37 | ENST00000706887.1 | |
MADD | NR_164835.1 | n.671C>T | non_coding_transcript_exon_variant | 3/37 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MADD | ENST00000706887.1 | c.469C>T | p.Pro157Ser | missense_variant | 3/37 | NM_001376571.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000414 AC: 63AN: 152256Hom.: 0 Cov.: 33
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?
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GnomAD3 exomes AF: 0.000537 AC: 135AN: 251208Hom.: 0 AF XY: 0.000560 AC XY: 76AN XY: 135782
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GnomAD4 exome AF: 0.000655 AC: 958AN: 1461812Hom.: 2 Cov.: 32 AF XY: 0.000644 AC XY: 468AN XY: 727216
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GnomAD4 genome ? AF: 0.000413 AC: 63AN: 152374Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40AN XY: 74522
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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 | May 03, 2022 | The c.469C>T (p.P157S) alteration is located in exon 3 (coding exon 2) of the MADD gene. This alteration results from a C to T substitution at nucleotide position 469, causing the proline (P) at amino acid position 157 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
0.67, 0.13, 0.11, 0.047, 1.0, 0.70, 0.19
.;P;B;B;B;D;.;P;B
Vest4
MVP
MPC
0.98
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