Variant 11-47274949-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001376571.1(MADD):c.449C>T(p.Thr150Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,742 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: 0.0000027 ( 0 hom. )

Consequence

MADD
NM_001376571.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.37

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]

MADD links:

MADD (HGNC:):

MADD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21287733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MADD	NM_001376571.1 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	3/37	NP_001363500.1
MADD	NM_003682.4 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	3/36	NP_003673.3	Q8WXG6-1
MADD	NM_001376572.1 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	3/37	NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	3/37			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251068

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

MADD: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

T;.;.;.;T;.;.;.;.

Eigen

Benign

0.074

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

.;N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D;D;D;D

REVEL

Benign

0.14

Sift

Benign

0.17

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T;T;T;T;T

Polyphen

0.41, 0.013, 0.039, 0.042, 0.35, 0.14, 0.068

.;B;B;B;B;B;.;B;B

Vest4

0.40

MutPred

0.19

Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);Loss of phosphorylation at T150 (P = 0.0062);

MVP

0.43

MPC

0.41

ClinPred

0.22

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over