rs1051006

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001376571.1(MADD):c.2251G>A(p.Val751Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,852 control chromosomes in the GnomAD database, including 41,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5998 hom., cov: 32)

Exomes 𝑓: 0.20 ( 35898 hom. )

Consequence

MADD
NM_001376571.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.831

Publications

60 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.0590674E-5).

BP6

Variant 11-47285034-G-A is Benign according to our data. Variant chr11-47285034-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376571.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MADD	NM_001376571.1	MANE Select	c.2251G>A	p.Val751Met	missense	Exon 13 of 37	NP_001363500.1
MADD	NM_003682.4		c.2251G>A	p.Val751Met	missense	Exon 13 of 36	NP_003673.3
MADD	NM_001376572.1		c.2251G>A	p.Val751Met	missense	Exon 13 of 37	NP_001363501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MADD	ENST00000706887.1	MANE Select	c.2251G>A	p.Val751Met	missense	Exon 13 of 37	ENSP00000516604.1
MADD	ENST00000311027.9	TSL:1	c.2251G>A	p.Val751Met	missense	Exon 13 of 36	ENSP00000310933.4
MADD	ENST00000349238.7	TSL:1	c.2251G>A	p.Val751Met	missense	Exon 13 of 34	ENSP00000304505.6

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39252

AN:

151880

Hom.:

5997

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.147

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.173

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.259

AC:

65051

AN:

251258

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.360

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.616

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.198

GnomAD4 exome

AF:

0.203

AC:

296050

AN:

1461854

Hom.:

35898

Cov.:

AF XY:

0.202

AC XY:

146574

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.357

AC:

11937

AN:

33480

American (AMR)

AF:

0.372

AC:

16622

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

3805

AN:

26136

East Asian (EAS)

AF:

0.604

AC:

23983

AN:

39700

South Asian (SAS)

AF:

0.236

AC:

20360

AN:

86258

European-Finnish (FIN)

AF:

0.269

AC:

14347

AN:

53382

Middle Eastern (MID)

AF:

0.159

AC:

919

AN:

5768

European-Non Finnish (NFE)

AF:

0.172

AC:

191521

AN:

1112010

Other (OTH)

AF:

0.208

AC:

12556

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14980

29960

44941

59921

74901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7282

14564

21846

29128

36410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.258

AC:

39267

AN:

151998

Hom.:

5998

Cov.:

AF XY:

0.267

AC XY:

19835

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.359

AC:

14888

AN:

41432

American (AMR)

AF:

0.273

AC:

4167

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

512

AN:

3472

East Asian (EAS)

AF:

0.594

AC:

3060

AN:

5150

South Asian (SAS)

AF:

0.238

AC:

1147

AN:

4822

European-Finnish (FIN)

AF:

0.297

AC:

3137

AN:

10552

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11749

AN:

67976

Other (OTH)

AF:

0.215

AC:

454

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1377

2755

4132

5510

6887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.196

Hom.:

12316

Bravo

AF:

0.264

TwinsUK

AF:

0.176

AC:

651

ALSPAC

AF:

0.177

AC:

681

ESP6500AA

AF:

0.345

AC:

1517

ESP6500EA

AF:

0.164

AC:

1414

ExAC

AF:

0.249

AC:

30218

Asia WGS

AF:

0.324

AC:

1124

AN:

3478

EpiCase

AF:

0.156

EpiControl

AF:

0.149

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.017

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.000021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.12

PhyloP100

-0.83

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.91

REVEL

Benign

0.089

Sift

Benign

0.19

Sift4G

Benign

0.25

Polyphen

0.19

Vest4

0.097

MPC

0.090

ClinPred

0.0026

GERP RS

-5.5

Varity_R

0.029

gMVP

0.28

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over