rs3736101

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001376571.1(MADD):c.2294G>A(p.Arg765Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,614,014 control chromosomes in the GnomAD database, including 8,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 520 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8224 hom. )

Consequence

MADD
NM_001376571.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.120

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014174283).

BP6

Variant 11-47285077-G-A is Benign according to our data. Variant chr11-47285077-G-A is described in ClinVar as [Benign]. Clinvar id is 1321157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
MADD	NM_001376571.1 link	c.2294G>A	p.Arg765Gln	missense_variant	Exon 13 of 37	NP_001363500.1
MADD	NM_003682.4 link	c.2294G>A	p.Arg765Gln	missense_variant	Exon 13 of 36	NP_003673.3	Q8WXG6-1
MADD	NM_001376572.1 link	c.2294G>A	p.Arg765Gln	missense_variant	Exon 13 of 37	NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1 link	c.2294G>A	p.Arg765Gln	missense_variant	Exon 13 of 37			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

AF:

0.0767

AC:

11664

AN:

152010

Hom.:

521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0355

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0630

Gnomad ASJ

AF:

0.0775

Gnomad EAS

AF:

0.0529

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0841

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0731

GnomAD3 exomes

AF:

0.0863

AC:

21692

AN:

251428

Hom.:

1093

AF XY:

0.0893

AC XY:

12136

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0379

Gnomad AMR exome

AF:

0.0354

Gnomad ASJ exome

AF:

0.0748

Gnomad EAS exome

AF:

0.0505

Gnomad SAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.0876

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.0915

GnomAD4 exome

AF:

0.103

AC:

150028

AN:

1461886

Hom.:

8224

Cov.:

AF XY:

0.103

AC XY:

74798

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0329

Gnomad4 AMR exome

AF:

0.0373

Gnomad4 ASJ exome

AF:

0.0757

Gnomad4 EAS exome

AF:

0.0525

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.0932

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.0951

GnomAD4 genome

AF:

0.0766

AC:

11660

AN:

152128

Hom.:

520

Cov.:

AF XY:

0.0754

AC XY:

5610

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0354

Gnomad4 AMR

AF:

0.0629

Gnomad4 ASJ

AF:

0.0775

Gnomad4 EAS

AF:

0.0528

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0841

Gnomad4 NFE

AF:

0.104

Gnomad4 OTH

AF:

0.0724

Alfa

AF:

0.0946

Hom.:

1425

Bravo

AF:

0.0714

TwinsUK

AF:

0.110

AC:

409

ALSPAC

AF:

0.113

AC:

437

ESP6500AA

AF:

0.0400

AC:

176

ESP6500EA

AF:

0.105

AC:

900

ExAC

AF:

0.0903

AC:

10970

Asia WGS

AF:

0.0770

AC:

267

AN:

3478

EpiCase

AF:

0.0994

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deeah syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MADD-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

T;.;T;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.93

D;D;D;D;D

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

.;N;N;N;N

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.080

N;N;N;N;N

REVEL

Benign

0.045

Sift

Benign

0.68

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0010, 0.0, 0.0050

.;B;B;B;B

Vest4

0.22

MPC

0.10

ClinPred

0.0089

GERP RS

0.70

Varity_R

0.022

gMVP

0.16

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