11-47269433-T-G

Variant names:

• chr11-47269433-T-G
• rs1449627
• ENST00000342922.8:c.-300T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 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: G2P, Ambry Genetics
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130470.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_130470.3		c.-300T>G		5_prime_UTR	Exon 1 of 33	NP_569826.2	A0A0A0MRB5
	MADD	NM_001376595.1		c.-300T>G		5_prime_UTR	Exon 1 of 36	NP_001363524.1	A0A9L9PXN0
	MADD	NM_001376641.1		c.-300T>G		5_prime_UTR	Exon 1 of 34	NP_001363570.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000342922.8	TSL:1	c.-300T>G		5_prime_UTR	Exon 1 of 33	ENSP00000343902.4	A0A0A0MRB5
	MADD	ENST00000922720.1		c.-300T>G		5_prime_UTR	Exon 1 of 34	ENSP00000592779.1
	MADD	ENST00000922718.1		c.-300T>G		5_prime_UTR	Exon 1 of 34	ENSP00000592777.1

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.833 AC: 5 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 8 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.338 AC: 27 AN: 80

Other (OTH) AF: 0.125 AC: 1 AN: 8

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

African (AFR) AF: 0.496 AC: 20603 AN: 41504

American (AMR) AF: 0.358 AC: 5472 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3468

East Asian (EAS) AF: 0.693 AC: 3577 AN: 5164

South Asian (SAS) AF: 0.467 AC: 2248 AN: 4818

European-Finnish (FIN) AF: 0.430 AC: 4553 AN: 10592

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21393 AN: 67966

Other (OTH) AF: 0.335 AC: 707 AN: 2110

Alfa AF: 0.328 Hom.: 17874

Bravo AF: 0.389

Asia WGS AF: 0.529 AC: 1835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.7
DANN	Benign	0.68
PhyloP100		0.17
PromoterAI		-0.011	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1449627; hg19: chr11-47290984;