rs2305280

Variant names:

• chr11-47328736-G-A
• rs2305280
• ENST00000706887.1:c.4848+32G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-47328736-G-A
• chr11-47328736-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000706887.1(MADD):​c.4848+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,612,942 control chromosomes in the GnomAD database, including 72,370 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 0.34 (9765 hom., cov: 33)
  • Exomes 𝑓: 0.28 (62605 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 26 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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4848+32G>A		intron_variant	Intron 36 of 36		NP_001363500.1
MADD	NM_003682.4	c.4839+32G>A		intron_variant	Intron 35 of 35		NP_003673.3
MADD	NM_001376572.1	c.4836+32G>A		intron_variant	Intron 36 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4848+32G>A		intron_variant	Intron 36 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51798 AN: 152052 Hom.: 9760 Cov.: 33

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.312

GnomAD2 exomes AF: 0.339 AC: 84608 AN: 249558 AF XY: 0.330

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.433

Gnomad ASJ exome AF: 0.293

Gnomad EAS exome AF: 0.650

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.279 AC: 408180 AN: 1460772 Hom.: 62605 Cov.: 36 AF XY: 0.281 AC XY: 203866 AN XY: 726652

African (AFR) AF: 0.464 AC: 15531 AN: 33472

American (AMR) AF: 0.420 AC: 18698 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7790 AN: 26134

East Asian (EAS) AF: 0.637 AC: 25250 AN: 39668

South Asian (SAS) AF: 0.363 AC: 31276 AN: 86172

European-Finnish (FIN) AF: 0.330 AC: 17576 AN: 53336

Middle Eastern (MID) AF: 0.289 AC: 1665 AN: 5766

European-Non Finnish (NFE) AF: 0.245 AC: 272595 AN: 1111382

Other (OTH) AF: 0.295 AC: 17799 AN: 60344

GnomAD4 genome AF: 0.341 AC: 51837 AN: 152170 Hom.: 9765 Cov.: 33 AF XY: 0.349 AC XY: 25976 AN XY: 74404

African (AFR) AF: 0.460 AC: 19117 AN: 41516

American (AMR) AF: 0.333 AC: 5093 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3468

East Asian (EAS) AF: 0.632 AC: 3273 AN: 5176

South Asian (SAS) AF: 0.367 AC: 1774 AN: 4834

European-Finnish (FIN) AF: 0.354 AC: 3742 AN: 10584

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16877 AN: 67996

Other (OTH) AF: 0.308 AC: 650 AN: 2108

Alfa AF: 0.276 Hom.: 8778

Bravo AF: 0.346

Asia WGS AF: 0.462 AC: 1606 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	1.9
DANN	Benign	0.65
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2305280; hg19: chr11-47350287; COSMIC: COSV57024912; COSMIC: COSV57024912;