dbSNP rs11039159: MADD:c.-88-1357G>T (chr11-47272470-G-T) – 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.-88-1357G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,192 control chromosomes in the GnomAD database, including 6,889 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 0.27 ( 6879 hom., cov: 31)

Exomes 𝑓: 0.30 ( 10 hom. )

Consequence

MADD
ENST00000706887.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.447

Publications

6 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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
MADD	NM_001376571.1 link	c.-88-1357G>T	intron_variant	Intron 1 of 36	NP_001363500.1
MADD	NM_003682.4 link	c.-88-1357G>T	intron_variant	Intron 1 of 35	NP_003673.3	Q8WXG6-1
MADD	NM_001376572.1 link	c.-88-1357G>T	intron_variant	Intron 1 of 36	NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1 link	c.-88-1357G>T		intron_variant	Intron 1 of 36			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41184

AN:

151908

Hom.:

6883

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.0216

Gnomad SAS

AF:

0.250

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.338

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.308

GnomAD4 exome

AF:

0.301

AC:

AN:

166

Hom.:

AF XY:

0.281

AC XY:

AN XY:

114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.300

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.333

AC:

AN:

120

Other (OTH)

AF:

0.292

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

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:

0.271

AC:

41178

AN:

152026

Hom.:

6879

Cov.:

AF XY:

0.265

AC XY:

19673

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.102

AC:

4217

AN:

41508

American (AMR)

AF:

0.247

AC:

3777

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

1322

AN:

3468

East Asian (EAS)

AF:

0.0218

AC:

113

AN:

5172

South Asian (SAS)

AF:

0.250

AC:

1201

AN:

4802

European-Finnish (FIN)

AF:

0.309

AC:

3262

AN:

10568

Middle Eastern (MID)

AF:

0.342

AC:

100

AN:

292

European-Non Finnish (NFE)

AF:

0.386

AC:

26219

AN:

67926

Other (OTH)

AF:

0.304

AC:

640

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1393

2786

4179

5572

6965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.335

Hom.:

3433

Bravo

AF:

0.258

Asia WGS

AF:

0.137

AC:

475

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.7

(source)

DANN

Benign

0.59

PhyloP100

0.45

PromoterAI

-0.0090

Neutral

(source)

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over