chr11-47328418-C-G

Variant names:

• chr11-47328418-C-G
• rs753993
• NM_001376571.1:c.4802-240C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376571.1(MADD):​c.4802-240C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104
• Publications: 15 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

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.4802-240C>G		intron	N/A	NP_001363500.1
	MADD	NM_003682.4		c.4793-240C>G		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.4790-240C>G		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.4802-240C>G		intron	N/A	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.4793-240C>G		intron	N/A	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.4676-240C>G		intron	N/A	ENSP00000304505.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1267830 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 613998

African (AFR) AF: 0.00 AC: 0 AN: 27860

American (AMR) AF: 0.00 AC: 0 AN: 18878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18436

East Asian (EAS) AF: 0.00 AC: 0 AN: 33712

South Asian (SAS) AF: 0.00 AC: 0 AN: 60722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3834

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023016

Other (OTH) AF: 0.00 AC: 0 AN: 52436

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.9
DANN	Benign	0.71
PhyloP100		0.10

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: rs753993; hg19: chr11-47349969;