Variant 11-47275092-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000706887.1(MADD):c.592C>T(p.Arg198Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MADD
ENST00000706887.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1 linkuse as main transcript	c.592C>T	p.Arg198Cys	missense_variant	3/37	ENST00000706887.1
MADD	NR_164835.1 linkuse as main transcript	n.794C>T		non_coding_transcript_exon_variant	3/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1 linkuse as main transcript	c.592C>T	p.Arg198Cys	missense_variant	3/37		NM_001376571.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250870

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135646

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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

Jun 09, 2022

The c.592C>T (p.R198C) 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 592, causing the arginine (R) at amino acid position 198 to be replaced by a cysteine (C). 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

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.21

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

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

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.87

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

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.3

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

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

.;D;D;D;D;D;.;D;D

Vest4

0.84

MutPred

0.67

Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);Gain of methylation at K197 (P = 0.0172);

MVP

0.54

MPC

1.3

ClinPred

0.97

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.76

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.

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