rs753992

Positions:

• chr11-47328295-G-A
• chr11-47328295-G-C

Variant summary

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

The ENST00000706887.1(MADD):​c.4802-363G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,158,666 control chromosomes in the GnomAD database, including 22,146 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 0.21 (3940 hom., cov: 33)
  • Exomes 𝑓: 0.18 (18206 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568

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 = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.4802-363G>A		intron_variant		ENST00000706887.1
MADD	NR_164835.1	n.5055-363G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.4802-363G>A		intron_variant			NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31941 AN: 151988 Hom.: 3934 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.182 AC: 182724 AN: 1006560 Hom.: 18206 Cov.: 32 AF XY: 0.182 AC XY: 86244 AN XY: 474940

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.210 AC: 31947 AN: 152106 Hom.: 3940 Cov.: 33 AF XY: 0.220 AC XY: 16347 AN XY: 74340

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.173

Alfa AF: 0.178 Hom.: 617

Bravo AF: 0.209

Asia WGS AF: 0.307 AC: 1066 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	6.5
DANN	Benign	0.72

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: rs753992; hg19: chr11-47349846;