rs753993

Positions:

• chr11-47328418-C-A
• chr11-47328418-C-G
• chr11-47328418-C-T

Variant summary

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

The ENST00000706887.1(MADD):​c.4802-240C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,419,240 control chromosomes in the GnomAD database, including 51,719 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 0.33 (10052 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41667 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104

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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.4802-240C>A		intron_variant		ENST00000706887.1
MADD	NR_164835.1	n.5055-240C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.4802-240C>A		intron_variant			NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50420 AN: 151912 Hom.: 10045 Cov.: 33

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.238 AC: 302030 AN: 1267206 Hom.: 41667 Cov.: 32 AF XY: 0.240 AC XY: 147205 AN XY: 613632

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.332 AC: 50457 AN: 152034 Hom.: 10052 Cov.: 33 AF XY: 0.340 AC XY: 25252 AN XY: 74298

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.634

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.270

Alfa AF: 0.309 Hom.: 1236

Bravo AF: 0.339

Asia WGS AF: 0.450 AC: 1564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.8
DANN	Benign	0.86

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: rs753993; hg19: chr11-47349969;