dbSNP rs11039183: MADD:c.4722+812G>A (chr11-47325389-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000706887.1(MADD):c.4722+812G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,506 control chromosomes in the GnomAD database, including 6,077 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 6047 hom., cov: 31)

Exomes 𝑓: 0.31 ( 30 hom. )

Consequence

MADD
ENST00000706887.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.972

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
MADD	NM_001376571.1 link	c.4722+812G>A	intron_variant	Intron 33 of 36	NP_001363500.1
MADD	NM_003682.4 link	c.4722+812G>A	intron_variant	Intron 33 of 35	NP_003673.3	Q8WXG6-1
MADD	NM_001376572.1 link	c.4710+812G>A	intron_variant	Intron 33 of 36	NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1 link	c.4722+812G>A		intron_variant	Intron 33 of 36			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38676

AN:

151886

Hom.:

6049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0970

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.358

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.299

Gnomad MID

AF:

0.303

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.284

GnomAD4 exome

AF:

0.309

AC:

155

AN:

502

Hom.:

AF XY:

0.316

AC XY:

AN XY:

310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.125

AC:

AN:

European-Finnish (FIN)

AF:

0.315

AC:

AN:

108

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.336

AC:

111

AN:

330

Other (OTH)

AF:

0.269

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.254

AC:

38676

AN:

152004

Hom.:

6047

Cov.:

AF XY:

0.249

AC XY:

18496

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0969

AC:

4018

AN:

41464

American (AMR)

AF:

0.231

AC:

3528

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.358

AC:

1241

AN:

3468

East Asian (EAS)

AF:

0.0213

AC:

110

AN:

5174

South Asian (SAS)

AF:

0.229

AC:

1103

AN:

4820

European-Finnish (FIN)

AF:

0.299

AC:

3161

AN:

10566

Middle Eastern (MID)

AF:

0.308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.361

AC:

24504

AN:

67950

Other (OTH)

AF:

0.281

AC:

594

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1387

2774

4161

5548

6935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.318

Hom.:

13026

Bravo

AF:

0.241

Asia WGS

AF:

0.128

AC:

447

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.4

(source)

DANN

Benign

0.70

PhyloP100

-0.97

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over