rs2290149

chr11-47324365-T-C

Variant summary

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

The ENST00000706887.1(MADD):c.4615+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,612,614 control chromosomes in the GnomAD database, including 16,335 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 0.11 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15331 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.4615+28T>C		intron_variant		ENST00000706887.1
MADD	NR_164835.1	n.4805+28T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.4615+28T>C		intron_variant			NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16282 AN: 152102 Hom.: 1008 Cov.: 32

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.0969

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.126 AC: 31624 AN: 250522 Hom.: 2405 AF XY: 0.133 AC XY: 18066 AN XY: 135396

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.0893

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.140 AC: 204030 AN: 1460394 Hom.: 15331 Cov.: 31 AF XY: 0.142 AC XY: 103368 AN XY: 726520

Gnomad4 AFR exome AF: 0.0554

Gnomad4 AMR exome AF: 0.0499

Gnomad4 ASJ exome AF: 0.0879

Gnomad4 EAS exome AF: 0.0879

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.107 AC: 16275 AN: 152220 Hom.: 1004 Cov.: 32 AF XY: 0.107 AC XY: 7956 AN XY: 74440

Gnomad4 AFR AF: 0.0571

Gnomad4 AMR AF: 0.0779

Gnomad4 ASJ AF: 0.0920

Gnomad4 EAS AF: 0.0962

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.103

Alfa AF: 0.131 Hom.: 813

Bravo AF: 0.0978

Asia WGS AF: 0.198 AC: 687 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.093
Dann	Benign	0.32

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: rs2290149; hg19: chr11-47345916; COSMIC: COSV60624359; COSMIC: COSV60624359;