11-47325709-C-T

Variant names:

• chr11-47325709-C-T
• rs7124958
• NM_001376571.1:c.4723-835C>T

Variant summary

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

The NM_001376571.1(MADD):​c.4723-835C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,172 control chromosomes in the GnomAD database, including 7,361 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 0.28 (7361 hom., cov: 33)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 13 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 = 0.579 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376571.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.4723-835C>T		intron	N/A	NP_001363500.1
	MADD	NM_003682.4		c.4723-1029C>T		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.4711-835C>T		intron	N/A	NP_001363501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.4723-835C>T		intron	N/A	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.4723-1029C>T		intron	N/A	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.4606-1029C>T		intron	N/A	ENSP00000304505.6

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42706 AN: 152054 Hom.: 7357 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.281 AC: 42737 AN: 152172 Hom.: 7361 Cov.: 33 AF XY: 0.289 AC XY: 21482 AN XY: 74388

African (AFR) AF: 0.435 AC: 18066 AN: 41492

American (AMR) AF: 0.278 AC: 4256 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3470

East Asian (EAS) AF: 0.596 AC: 3085 AN: 5174

South Asian (SAS) AF: 0.236 AC: 1142 AN: 4830

European-Finnish (FIN) AF: 0.299 AC: 3164 AN: 10590

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11790 AN: 68002

Other (OTH) AF: 0.229 AC: 484 AN: 2112

Alfa AF: 0.245 Hom.: 1430

Bravo AF: 0.289

Asia WGS AF: 0.332 AC: 1153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.7
DANN	Benign	0.52
PhyloP100		0.035
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: rs7124958; hg19: chr11-47347260;