ENST00000706887.1:c.1210-121T>C

Variant names:

• chr11-47278878-T-C
• rs4752977
• NM_001376571.1:c.1210-121T>C

Variant summary

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

The ENST00000706887.1(MADD):​c.1210-121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 717,986 control chromosomes in the GnomAD database, including 25,644 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 0.28 (7400 hom., cov: 32)
  • Exomes 𝑓: 0.22 (18244 hom.)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• Publications: 24 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000706887.1. 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_001376571.1	MANE Select	c.1210-121T>C		intron	N/A	NP_001363500.1	A0A9L9PXF1
	MADD	NM_003682.4		c.1210-121T>C		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.1210-121T>C		intron	N/A	NP_001363501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.1210-121T>C		intron	N/A	ENSP00000516604.1	A0A9L9PXF1
	MADD	ENST00000311027.9	TSL:1	c.1210-121T>C		intron	N/A	ENSP00000310933.4	Q8WXG6-1
	MADD	ENST00000349238.7	TSL:1	c.1210-121T>C		intron	N/A	ENSP00000304505.6	Q8WXG6-2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42719 AN: 151978 Hom.: 7394 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.224 AC: 126801 AN: 565890 Hom.: 18244 AF XY: 0.222 AC XY: 66629 AN XY: 300268

African (AFR) AF: 0.432 AC: 6286 AN: 14558

American (AMR) AF: 0.355 AC: 9055 AN: 25514

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 2471 AN: 16876

East Asian (EAS) AF: 0.607 AC: 18443 AN: 30406

South Asian (SAS) AF: 0.241 AC: 12687 AN: 52614

European-Finnish (FIN) AF: 0.271 AC: 11951 AN: 44060

Middle Eastern (MID) AF: 0.175 AC: 493 AN: 2816

European-Non Finnish (NFE) AF: 0.169 AC: 59120 AN: 349882

Other (OTH) AF: 0.216 AC: 6295 AN: 29164

GnomAD4 genome AF: 0.281 AC: 42751 AN: 152096 Hom.: 7400 Cov.: 32 AF XY: 0.289 AC XY: 21494 AN XY: 74358

African (AFR) AF: 0.439 AC: 18193 AN: 41466

American (AMR) AF: 0.279 AC: 4257 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3470

East Asian (EAS) AF: 0.598 AC: 3090 AN: 5170

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4822

European-Finnish (FIN) AF: 0.297 AC: 3136 AN: 10564

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11770 AN: 68010

Other (OTH) AF: 0.230 AC: 487 AN: 2116

Alfa AF: 0.261 Hom.: 2088

Bravo AF: 0.289

Asia WGS AF: 0.334 AC: 1157 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.81
DANN	Benign	0.39
PhyloP100		-0.47
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: rs4752977; hg19: chr11-47300429;