11-47272248-G-C

Variant names:

• chr11-47272248-G-C
• rs10501320
• NM_001376571.1:c.-88-1579G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001376571.1(MADD):​c.-88-1579G>C variant causes a intron change. The variant allele was found at a frequency of 0.173 in 152,150 control chromosomes in the GnomAD database, including 3,064 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 0.17 (3064 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• Publications: 57 publications found

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]

MADD-AS1 (HGNC:40354): (MADD antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376571.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.-88-1579G>C		intron	N/A	NP_001363500.1
	MADD	NM_003682.4		c.-88-1579G>C		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.-88-1579G>C		intron	N/A	NP_001363501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.-88-1579G>C		intron	N/A	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.-88-1579G>C		intron	N/A	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.-88-1579G>C		intron	N/A	ENSP00000304505.6

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26280 AN: 152028 Hom.: 3065 Cov.: 32

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.173 AC: 26277 AN: 152146 Hom.: 3064 Cov.: 32 AF XY: 0.166 AC XY: 12342 AN XY: 74380

African (AFR) AF: 0.0437 AC: 1813 AN: 41508

American (AMR) AF: 0.173 AC: 2649 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 990 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0822 AC: 397 AN: 4830

European-Finnish (FIN) AF: 0.176 AC: 1860 AN: 10588

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17905 AN: 67974

Other (OTH) AF: 0.209 AC: 440 AN: 2108

Alfa AF: 0.216 Hom.: 505

Bravo AF: 0.168

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.93
PhyloP100		6.0
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10501320; hg19: chr11-47293799;