rs2290149

Variant names:

• chr11-47324365-T-C
• rs2290149
• ENST00000706887.1:c.4615+28T>C

Variant summary

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

The ENST00000706887.1(MADD):​c.4615+28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,612,614 control chromosomes in the GnomAD database, including 16,335 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 0.11 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15331 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 20 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

ENSG00000283338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4615+28T>C		intron_variant	Intron 32 of 36		NP_001363500.1
MADD	NM_003682.4	c.4615+28T>C		intron_variant	Intron 32 of 35		NP_003673.3
MADD	NM_001376572.1	c.4603+28T>C		intron_variant	Intron 32 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4615+28T>C		intron_variant	Intron 32 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16282 AN: 152102 Hom.: 1008 Cov.: 32

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.0969

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.126 AC: 31624 AN: 250522 AF XY: 0.133

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.0893

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.140 AC: 204030 AN: 1460394 Hom.: 15331 Cov.: 31 AF XY: 0.142 AC XY: 103368 AN XY: 726520

African (AFR) AF: 0.0554 AC: 1852 AN: 33456

American (AMR) AF: 0.0499 AC: 2230 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 2297 AN: 26124

East Asian (EAS) AF: 0.0879 AC: 3490 AN: 39684

South Asian (SAS) AF: 0.226 AC: 19510 AN: 86196

European-Finnish (FIN) AF: 0.130 AC: 6956 AN: 53380

Middle Eastern (MID) AF: 0.0964 AC: 556 AN: 5766

European-Non Finnish (NFE) AF: 0.143 AC: 159040 AN: 1110724

Other (OTH) AF: 0.134 AC: 8099 AN: 60360

GnomAD4 genome AF: 0.107 AC: 16275 AN: 152220 Hom.: 1004 Cov.: 32 AF XY: 0.107 AC XY: 7956 AN XY: 74440

African (AFR) AF: 0.0571 AC: 2372 AN: 41528

American (AMR) AF: 0.0779 AC: 1191 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 319 AN: 3468

East Asian (EAS) AF: 0.0962 AC: 498 AN: 5178

South Asian (SAS) AF: 0.229 AC: 1106 AN: 4826

European-Finnish (FIN) AF: 0.116 AC: 1227 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9272 AN: 67994

Other (OTH) AF: 0.103 AC: 217 AN: 2112

Alfa AF: 0.131 Hom.: 880

Bravo AF: 0.0978

Asia WGS AF: 0.198 AC: 687 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.093
DANN	Benign	0.32
PhyloP100		-2.0
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: rs2290149; hg19: chr11-47345916; COSMIC: COSV60624359; COSMIC: COSV60624359;