11-47274982-G-A

Position:

chr11-47274982-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001376571.1(MADD):c.482G>A(p.Arg161His) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,614,138 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 8 hom. )

Consequence

MADD
NM_001376571.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.28

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:

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=0.00607574).

BP6

Variant 11-47274982-G-A is Benign according to our data. Variant chr11-47274982-G-A is described in ClinVar as [Benign]. Clinvar id is 779197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00649 (989/152336) while in subpopulation AFR AF= 0.0227 (945/41574). AF 95% confidence interval is 0.0215. There are 13 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
MADD	NM_001376571.1 linkuse as main transcript	c.482G>A	p.Arg161His	missense_variant	3/37	NP_001363500.1
MADD	NM_003682.4 linkuse as main transcript	c.482G>A	p.Arg161His	missense_variant	3/36	NP_003673.3	Q8WXG6-1
MADD	NM_001376572.1 linkuse as main transcript	c.482G>A	p.Arg161His	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.482G>A	p.Arg161His	missense_variant	3/37			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

AF:

0.00649

AC:

988

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00180

AC:

452

AN:

251152

Hom.:

AF XY:

0.00111

AC XY:

151

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0238

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000800

AC:

1169

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000653

AC XY:

475

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0268

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00649

AC:

989

AN:

152336

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

474

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0227

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.000823

Hom.:

Bravo

AF:

0.00755

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2018	- -

MADD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

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

MetaRNN

Benign

0.0061

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

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.55

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

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.5

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

REVEL

Benign

0.22

Sift

Benign

0.054

T;T;T;D;D;T;T;D;T

Sift4G

Benign

0.063

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

Polyphen

1.0, 0.90, 0.84, 1.0, 0.99, 0.95

.;D;D;P;P;D;.;D;P

Vest4

0.21

MVP

0.39

MPC

0.43

ClinPred

0.043

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.35

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