chr11-47291341-T-G

Variant names:

• chr11-47291341-T-G
• rs10838687
• ENST00000706887.1:c.3361+525T>G

Variant summary

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

The ENST00000706887.1(MADD):​c.3361+525T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,020 control chromosomes in the GnomAD database, including 8,776 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 0.31 (8776 hom., cov: 31)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 55 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.3361+525T>G		intron_variant	Intron 20 of 36		NP_001363500.1
MADD	NM_003682.4	c.3361+525T>G		intron_variant	Intron 20 of 35		NP_003673.3
MADD	NM_001376572.1	c.3361+525T>G		intron_variant	Intron 20 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.3361+525T>G		intron_variant	Intron 20 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47802 AN: 151902 Hom.: 8775 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.315 AC: 47831 AN: 152020 Hom.: 8776 Cov.: 31 AF XY: 0.324 AC XY: 24092 AN XY: 74308

African (AFR) AF: 0.460 AC: 19049 AN: 41436

American (AMR) AF: 0.295 AC: 4506 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3470

East Asian (EAS) AF: 0.640 AC: 3298 AN: 5156

South Asian (SAS) AF: 0.354 AC: 1703 AN: 4810

European-Finnish (FIN) AF: 0.345 AC: 3643 AN: 10568

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14330 AN: 67982

Other (OTH) AF: 0.262 AC: 553 AN: 2110

Alfa AF: 0.243 Hom.: 22064

Bravo AF: 0.317

Asia WGS AF: 0.450 AC: 1564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.43
PhyloP100		0.033
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: rs10838687; hg19: chr11-47312892;