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GeneBe

11-47274607-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000706887.1(MADD):c.107G>A(p.Arg36Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

MADD
ENST00000706887.1 missense

Scores

7
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MADDNM_001376571.1 linkuse as main transcriptc.107G>A p.Arg36Gln missense_variant 3/37 ENST00000706887.1
MADDNR_164835.1 linkuse as main transcriptn.309G>A non_coding_transcript_exon_variant 3/37

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MADDENST00000706887.1 linkuse as main transcriptc.107G>A p.Arg36Gln missense_variant 3/37 NM_001376571.1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152136
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251376
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000479
AC:
70
AN:
1461796
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000567
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152136
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000965
Hom.:
0
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsAug 17, 2021The c.107G>A (p.R36Q) alteration is located in exon 3 (coding exon 2) of the MADD gene. This alteration results from a G to A substitution at nucleotide position 107, causing the arginine (R) at amino acid position 36 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Uncertain
-0.020
Cadd
Pathogenic
29
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.083
T;T;.;.;.;T;.;.;.;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.74
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.65
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.99, 1.0
.;.;D;D;D;D;D;.;.;D;D;.
Vest4
0.69, 0.64, 0.67, 0.63, 0.64, 0.68, 0.72, 0.62, 0.69
MVP
0.59
MPC
1.2
ClinPred
0.94
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.53
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748229155; hg19: chr11-47296158; API