11-47328418-C-T

Variant names:

• chr11-47328418-C-T
• rs753993
• ENST00000469699.1:n.277C>T

Variant summary

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

The ENST00000469699.1(MADD):​n.277C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 1,267,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000024 (0 hom.)
• Consequence: MADD ENST00000469699.1 non_coding_transcript_exon
• 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=-0.68).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4802-240C>T		intron_variant	Intron 35 of 36		NP_001363500.1
MADD	NM_003682.4	c.4793-240C>T		intron_variant	Intron 34 of 35		NP_003673.3
MADD	NM_001376572.1	c.4790-240C>T		intron_variant	Intron 35 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4802-240C>T		intron_variant	Intron 35 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1267832 Hom.: 0 Cov.: 32 AF XY: 0.00000163 AC XY: 1 AN XY: 614000

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: 0.00000293 AC: 3 AN: 1023018

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;