rs7944584

Variant names:

• chr11-47314769-A-T
• rs7944584
• NM_001376571.1:c.4270-451A>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.4270-451A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,248 control chromosomes in the GnomAD database, including 3,494 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 0.19 (3494 hom., cov: 32)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.750
• Publications: 108 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.4270-451A>T		intron	N/A	NP_001363500.1
	MADD	NM_003682.4		c.4270-451A>T		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.4258-451A>T		intron	N/A	NP_001363501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.4270-451A>T		intron	N/A	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.4270-451A>T		intron	N/A	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.4153-451A>T		intron	N/A	ENSP00000304505.6

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28329 AN: 152130 Hom.: 3495 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.186 AC: 28324 AN: 152248 Hom.: 3494 Cov.: 32 AF XY: 0.181 AC XY: 13435 AN XY: 74428

African (AFR) AF: 0.0466 AC: 1938 AN: 41574

American (AMR) AF: 0.185 AC: 2825 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3472

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5190

South Asian (SAS) AF: 0.195 AC: 938 AN: 4820

European-Finnish (FIN) AF: 0.178 AC: 1885 AN: 10602

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18924 AN: 67990

Other (OTH) AF: 0.222 AC: 467 AN: 2108

Alfa AF: 0.256 Hom.: 2992

Bravo AF: 0.179

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.75
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: rs7944584; hg19: chr11-47336320;