chr11-47296606-T-C

Variant names:

• chr11-47296606-T-C
• rs749067
• ENST00000706887.1:c.3759+551T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000706887.1(MADD):​c.3759+551T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,038 control chromosomes in the GnomAD database, including 6,801 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 0.26 (6801 hom., cov: 31)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 18 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.3759+551T>C		intron_variant	Intron 24 of 36		NP_001363500.1
MADD	NM_003682.4	c.3759+551T>C		intron_variant	Intron 24 of 35		NP_003673.3
MADD	NM_001376572.1	c.3747+551T>C		intron_variant	Intron 24 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.3759+551T>C		intron_variant	Intron 24 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39796 AN: 151920 Hom.: 6805 Cov.: 31

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.262 AC: 39783 AN: 152038 Hom.: 6801 Cov.: 31 AF XY: 0.256 AC XY: 19035 AN XY: 74306

African (AFR) AF: 0.0658 AC: 2733 AN: 41528

American (AMR) AF: 0.247 AC: 3769 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1322 AN: 3464

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.253 AC: 1219 AN: 4816

European-Finnish (FIN) AF: 0.310 AC: 3262 AN: 10526

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26302 AN: 67944

Other (OTH) AF: 0.297 AC: 627 AN: 2112

Alfa AF: 0.356 Hom.: 17487

Bravo AF: 0.247

Asia WGS AF: 0.133 AC: 464 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.73
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs749067; hg19: chr11-47318157;