11-47325709-C-T

Variant summary

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

The ENST00000706887.1(MADD):c.4723-835C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,172 control chromosomes in the GnomAD database, including 7,361 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 0.28 (7361 hom., cov: 33)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.4723-835C>T		intron_variant		ENST00000706887.1
MADD	NR_164835.1	n.4984+376C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.4723-835C>T		intron_variant			NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42706 AN: 152054 Hom.: 7357 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.233

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.281 AC: 42737 AN: 152172 Hom.: 7361 Cov.: 33 AF XY: 0.289 AC XY: 21482 AN XY: 74388

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.229

Alfa AF: 0.120 Hom.: 207

Bravo AF: 0.289

Asia WGS AF: 0.332 AC: 1153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.7
Dann	Benign	0.52

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: rs7124958; hg19: chr11-47347260;