Genetic Variant MADD:c.-300T>G (chr11-47269433-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000342922.8(MADD):c.-300T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,230 control chromosomes in the GnomAD database, including 12,564 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 0.39 ( 12554 hom., cov: 33)

Exomes 𝑓: 0.39 ( 10 hom. )

Consequence

MADD
ENST00000342922.8 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.173

Publications

27 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=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
MADD	NM_130470.3 link	c.-300T>G	5_prime_UTR_variant	Exon 1 of 33	NP_569826.2
MADD	NM_001376595.1 link	c.-300T>G	5_prime_UTR_variant	Exon 1 of 36	NP_001363524.1
MADD	NM_001376641.1 link	c.-300T>G	5_prime_UTR_variant	Exon 1 of 34	NP_001363570.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
MADD	ENST00000342922.8 link	c.-300T>G	5_prime_UTR_variant	Exon 1 of 33	1	ENSP00000343902.4
MADD	ENST00000453571.5 link	c.-89+150T>G	intron_variant	Intron 1 of 2	4	ENSP00000388255.1
MADD	ENST00000311027.9 link	c.-406T>G	upstream_gene_variant		1	ENSP00000310933.4

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59596

AN:

152002

Hom.:

12554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.692

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.430

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.339

GnomAD4 exome

AF:

0.391

AC:

AN:

110

Hom.:

Cov.:

AF XY:

0.362

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.833

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.338

AC:

AN:

Other (OTH)

AF:

0.125

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.392

AC:

59621

AN:

152120

Hom.:

12554

Cov.:

AF XY:

0.400

AC XY:

29783

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.496

AC:

20603

AN:

41504

American (AMR)

AF:

0.358

AC:

5472

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

836

AN:

3468

East Asian (EAS)

AF:

0.693

AC:

3577

AN:

5164

South Asian (SAS)

AF:

0.467

AC:

2248

AN:

4818

European-Finnish (FIN)

AF:

0.430

AC:

4553

AN:

10592

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21393

AN:

67966

Other (OTH)

AF:

0.335

AC:

707

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1867

3735

5602

7470

9337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.328

Hom.:

17874

Bravo

AF:

0.389

Asia WGS

AF:

0.529

AC:

1835

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.7

(source)

DANN

Benign

0.68

PhyloP100

0.17

PromoterAI

-0.011

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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