rs11039179

Positions:

• chr11-47324248-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000706887.1(MADD):​c.4543-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,894 control chromosomes in the GnomAD database, including 1,134 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 0.021 (76 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1058 hom.)
• Consequence: MADD ENST00000706887.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4543-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000706887.1	NP_001363500.1
MADD	NR_164835.1	n.4733-17C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4543-17C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_001376571.1	ENSP00000516604

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3248 AN: 152248 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.0331 AC: 8294 AN: 250404 Hom.: 295 AF XY: 0.0373 AC XY: 5054 AN XY: 135346

Gnomad AFR exome AF: 0.00550

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.0382

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0297 AC: 43403 AN: 1460528 Hom.: 1058 Cov.: 31 AF XY: 0.0321 AC XY: 23299 AN XY: 726618

Gnomad4 AFR exome AF: 0.00409

Gnomad4 AMR exome AF: 0.00872

Gnomad4 ASJ exome AF: 0.00433

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0213 AC: 3239 AN: 152366 Hom.: 76 Cov.: 32 AF XY: 0.0228 AC XY: 1697 AN XY: 74510

Gnomad4 AFR AF: 0.00531

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0207 Hom.: 9

Bravo AF: 0.0172

Asia WGS AF: 0.110 AC: 384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs11039179; hg19: chr11-47345799;