chr11-47324248-C-T

Variant names:

• chr11-47324248-C-T
• rs11039179
• NM_001376571.1:c.4543-17C>T

Variant summary

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

The NM_001376571.1(MADD):​c.4543-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,894 control chromosomes in the GnomAD database, including 1,134 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 0.021 (76 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1058 hom.)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 7 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

ENSG00000283338 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.4543-17C>T		intron	N/A	NP_001363500.1	A0A9L9PXF1
	MADD	NM_003682.4		c.4543-17C>T		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.4531-17C>T		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.4543-17C>T		intron	N/A	ENSP00000516604.1	A0A9L9PXF1
	MADD	ENST00000311027.9	TSL:1	c.4543-17C>T		intron	N/A	ENSP00000310933.4	Q8WXG6-1
	MADD	ENST00000349238.7	TSL:1	c.4426-17C>T		intron	N/A	ENSP00000304505.6	Q8WXG6-2

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3248 AN: 152248 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0331 AC: 8294 AN: 250404 AF XY: 0.0373

Gnomad AFR exome AF: 0.00550

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0297 AC: 43403 AN: 1460528 Hom.: 1058 Cov.: 31 AF XY: 0.0321 AC XY: 23299 AN XY: 726618

African (AFR) AF: 0.00409 AC: 137 AN: 33456

American (AMR) AF: 0.00872 AC: 390 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 113 AN: 26114

East Asian (EAS) AF: 0.0352 AC: 1395 AN: 39672

South Asian (SAS) AF: 0.107 AC: 9185 AN: 86178

European-Finnish (FIN) AF: 0.0342 AC: 1824 AN: 53390

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5766

European-Non Finnish (NFE) AF: 0.0256 AC: 28433 AN: 1110920

Other (OTH) AF: 0.0310 AC: 1871 AN: 60320

GnomAD4 genome AF: 0.0213 AC: 3239 AN: 152366 Hom.: 76 Cov.: 32 AF XY: 0.0228 AC XY: 1697 AN XY: 74510

African (AFR) AF: 0.00531 AC: 221 AN: 41586

American (AMR) AF: 0.0115 AC: 176 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0422 AC: 219 AN: 5190

South Asian (SAS) AF: 0.112 AC: 542 AN: 4830

European-Finnish (FIN) AF: 0.0269 AC: 286 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1708 AN: 68034

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0249 Hom.: 78

Bravo AF: 0.0172

Asia WGS AF: 0.110 AC: 384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.64
PhyloP100		0.014
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: rs11039179; hg19: chr11-47345799;