chr11-47269433-T-G

Variant names:

• chr11-47269433-T-G
• rs1449627
• ENST00000342922:c.-300T>G

Variant summary

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

The NM_130470.3(MADD):​c.-300T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,230 control chromosomes in the GnomAD database, including 12,564 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 (12554 hom., cov: 33)
  • Exomes 𝑓: 0.39 (10 hom.)
• Consequence: MADD NM_130470.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173

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=-0.79).
• 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 rank	MANE	Protein	UniProt
MADD	NM_130470.3	c.-300T>G		5_prime_UTR_variant	Exon 1 of 33		NP_569826.2
MADD	NM_001376595.1	c.-300T>G		5_prime_UTR_variant	Exon 1 of 36		NP_001363524.1
MADD	NM_001376641.1	c.-300T>G		5_prime_UTR_variant	Exon 1 of 34		NP_001363570.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000342922	c.-300T>G		5_prime_UTR_variant	Exon 1 of 33	1		ENSP00000343902.4
MADD	ENST00000453571.5	c.-89+150T>G		intron_variant	Intron 1 of 2	4		ENSP00000388255.1
MADD	ENST00000311027.9	c.-406T>G		upstream_gene_variant		1		ENSP00000310933.4

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59596 AN: 152002 Hom.: 12554 Cov.: 33

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.339

GnomAD4 exome AF: 0.391 AC: 43 AN: 110 Hom.: 10 Cov.: 0 AF XY: 0.362 AC XY: 29 AN XY: 80

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.392 AC: 59621 AN: 152120 Hom.: 12554 Cov.: 33 AF XY: 0.400 AC XY: 29783 AN XY: 74366

Gnomad4 AFR AF: 0.496

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.693

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.335

Alfa AF: 0.307 Hom.: 10316

Bravo AF: 0.389

Asia WGS AF: 0.529 AC: 1835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.7
DANN	Benign	0.68

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1449627; hg19: chr11-47290984;