11-47274969-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001376571.1(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
NM_001376571.1 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.045625865).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000413 (63/152374) while in subpopulation NFE AF= 0.000544 (37/68026). AF 95% confidence interval is 0.000405. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MADDNM_001376571.1 linkc.469C>T p.Pro157Ser missense_variant Exon 3 of 37 NP_001363500.1
MADDNM_003682.4 linkc.469C>T p.Pro157Ser missense_variant Exon 3 of 36 NP_003673.3 Q8WXG6-1
MADDNM_001376572.1 linkc.469C>T p.Pro157Ser missense_variant Exon 3 of 37 NP_001363501.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MADDENST00000706887.1 linkc.469C>T p.Pro157Ser missense_variant Exon 3 of 37 ENSP00000516604.1 A0A9L9PXF1

Frequencies

GnomAD3 genomes
AF:
0.000414
AC:
63
AN:
152256
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000289
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:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000537
AC:
135
AN:
251208
Hom.:
0
AF XY:
0.000560
AC XY:
76
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000882
Gnomad NFE exome
AF:
0.000951
Gnomad OTH exome
AF:
0.000816
GnomAD4 exome
AF:
0.000655
AC:
958
AN:
1461812
Hom.:
2
Cov.:
32
AF XY:
0.000644
AC XY:
468
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000975
Gnomad4 NFE exome
AF:
0.000769
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.000413
AC:
63
AN:
152374
Hom.:
0
Cov.:
33
AF XY:
0.000537
AC XY:
40
AN XY:
74522
show subpopulations
Gnomad4 AFR
AF:
0.000288
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00132
Gnomad4 NFE
AF:
0.000544
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000590
Hom.:
0
Bravo
AF:
0.000325
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000642
AC:
78
EpiCase
AF:
0.000709
EpiControl
AF:
0.000711

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
May 03, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.36
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.076
T;.;.;.;T;.;.;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.046
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.55
.;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.6
D;D;D;D;D;D;D;D;D
REVEL
Benign
0.19
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.026
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
0.46
MVP
0.34
MPC
0.98
ClinPred
0.16
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.56

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: rs187671926; hg19: chr11-47296520; COSMIC: COSV104598544; COSMIC: COSV104598544; API