chr11-47312973-G-A

Variant names:

• chr11-47312973-G-A
• rs10838689
• ENST00000706887.1:c.4269+1131G>A

Variant summary

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

The ENST00000706887.1(MADD):​c.4269+1131G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,072 control chromosomes in the GnomAD database, including 5,758 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 0.25 (5758 hom., cov: 32)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4269+1131G>A		intron_variant	Intron 29 of 36		NP_001363500.1
MADD	NM_003682.4	c.4269+1131G>A		intron_variant	Intron 29 of 35		NP_003673.3
MADD	NM_001376572.1	c.4257+1131G>A		intron_variant	Intron 29 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4269+1131G>A		intron_variant	Intron 29 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38694 AN: 151954 Hom.: 5759 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.255 AC: 38703 AN: 152072 Hom.: 5758 Cov.: 32 AF XY: 0.264 AC XY: 19601 AN XY: 74336

African (AFR) AF: 0.344 AC: 14258 AN: 41470

American (AMR) AF: 0.271 AC: 4139 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 584 AN: 3472

East Asian (EAS) AF: 0.592 AC: 3064 AN: 5176

South Asian (SAS) AF: 0.238 AC: 1148 AN: 4828

European-Finnish (FIN) AF: 0.298 AC: 3145 AN: 10542

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11775 AN: 67988

Other (OTH) AF: 0.207 AC: 438 AN: 2114

Alfa AF: 0.255 Hom.: 1536

Bravo AF: 0.259

Asia WGS AF: 0.321 AC: 1113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		-0.048
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: rs10838689; hg19: chr11-47334524; COSMIC: COSV107317590; COSMIC: COSV107317590;