11-47274969-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001376571.1(MADD):c.469C>T(p.Pro157Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000633 in 1,614,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 2 hom. )

Consequence

MADD
NM_001376571.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.62

Publications

2 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: G2P, Ambry Genetics
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045625865).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000413 (63/152374) while in subpopulation NFE AF = 0.000544 (37/68026). AF 95% confidence interval is 0.000405. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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	UniProt
MADD	NM_001376571.1	MANE Select	c.469C>T	p.Pro157Ser	missense	Exon 3 of 37	NP_001363500.1	A0A9L9PXF1
MADD	NM_003682.4		c.469C>T	p.Pro157Ser	missense	Exon 3 of 36	NP_003673.3
MADD	NM_001376572.1		c.469C>T	p.Pro157Ser	missense	Exon 3 of 37	NP_001363501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MADD	ENST00000706887.1	MANE Select	c.469C>T	p.Pro157Ser	missense	Exon 3 of 37	ENSP00000516604.1	A0A9L9PXF1
MADD	ENST00000311027.9	TSL:1	c.469C>T	p.Pro157Ser	missense	Exon 3 of 36	ENSP00000310933.4	Q8WXG6-1
MADD	ENST00000349238.7	TSL:1	c.469C>T	p.Pro157Ser	missense	Exon 3 of 34	ENSP00000304505.6	Q8WXG6-2

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000537

AC:

135

AN:

251208

AF XY:

0.000560

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000882

Gnomad NFE exome

AF:

0.000951

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000655

AC:

958

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

468

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000975

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000769

AC:

855

AN:

1112000

Other (OTH)

AF:

0.000679

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000413

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000288

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000671

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000642

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.019

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

5.6

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.026

Polyphen

0.67

Vest4

0.46

MVP

0.34

MPC

0.98

ClinPred

0.16

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.56

Mutation Taster

=37/63

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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