11-47323549-T-C

Position:

• chr11-47323549-T-C

Variant summary

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

The ENST00000706887.1(MADD):​c.4378-122T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 919,454 control chromosomes in the GnomAD database, including 67,017 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 0.39 (12568 hom., cov: 32)
  • Exomes 𝑓: 0.36 (54449 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4378-122T>C		intron_variant		ENST00000706887.1	NP_001363500.1
MADD	NR_164835.1	n.4568-122T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4378-122T>C		intron_variant			NM_001376571.1	ENSP00000516604

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59618 AN: 151916 Hom.: 12569 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.364 AC: 279277 AN: 767420 Hom.: 54449 AF XY: 0.365 AC XY: 143131 AN XY: 391728

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.693

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.410

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.392 AC: 59643 AN: 152034 Hom.: 12568 Cov.: 32 AF XY: 0.401 AC XY: 29785 AN XY: 74312

Gnomad4 AFR AF: 0.496

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.336

Alfa AF: 0.337 Hom.: 4464

Bravo AF: 0.390

Asia WGS AF: 0.531 AC: 1842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs10838692; hg19: chr11-47345100; COSMIC: COSV60623141; COSMIC: COSV60623141;