11-47285079-C-T

Variant names:

• chr11-47285079-C-T
• rs35233100
• ENST00000706887.1:c.2296C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BA1

The ENST00000706887.1(MADD):​c.2296C>T​(p.Arg766*) variant causes a stop gained change. The variant allele was found at a frequency of 0.052 in 1,614,010 control chromosomes in the GnomAD database, including 2,579 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.039 (183 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2396 hom.)
• Consequence: MADD ENST00000706887.1 stop_gained
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.27
• Publications: 48 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 11-47285079-C-T is Benign according to our data. Variant chr11-47285079-C-T is described in ClinVar as Benign. ClinVar VariationId is 3037635.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.2296C>T	p.Arg766*	stop_gained	Exon 13 of 37		NP_001363500.1
MADD	NM_003682.4	c.2296C>T	p.Arg766*	stop_gained	Exon 13 of 36		NP_003673.3
MADD	NM_001376572.1	c.2296C>T	p.Arg766*	stop_gained	Exon 13 of 37		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.2296C>T	p.Arg766*	stop_gained	Exon 13 of 37			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5867 AN: 152018 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.00998

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0265

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0385 AC: 9671 AN: 251450 AF XY: 0.0390

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0389

Gnomad NFE exome AF: 0.0607

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0534 AC: 78096 AN: 1461874 Hom.: 2396 Cov.: 33 AF XY: 0.0520 AC XY: 37845 AN XY: 727236

African (AFR) AF: 0.00792 AC: 265 AN: 33480

American (AMR) AF: 0.0235 AC: 1050 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 850 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0148 AC: 1273 AN: 86258

European-Finnish (FIN) AF: 0.0394 AC: 2105 AN: 53402

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0627 AC: 69680 AN: 1112010

Other (OTH) AF: 0.0444 AC: 2680 AN: 60396

GnomAD4 genome AF: 0.0385 AC: 5863 AN: 152136 Hom.: 183 Cov.: 32 AF XY: 0.0358 AC XY: 2666 AN XY: 74368

African (AFR) AF: 0.00995 AC: 413 AN: 41522

American (AMR) AF: 0.0264 AC: 404 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4814

European-Finnish (FIN) AF: 0.0367 AC: 388 AN: 10570

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0627 AC: 4266 AN: 67998

Other (OTH) AF: 0.0517 AC: 109 AN: 2110

Alfa AF: 0.0511 Hom.: 755

Bravo AF: 0.0363

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0599 AC: 231

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0634 AC: 545

ExAC AF: 0.0393 AC: 4775

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0568

EpiControl AF: 0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MADD-related disorder Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.3
Vest4		0.77
GERP RS		4.1
Mutation Taster		=163/37	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35233100; hg19: chr11-47306630; COSMIC: COSV107317579; COSMIC: COSV107317579;