11-47273075-T-C

Variant names:

• chr11-47273075-T-C
• rs10501321
• ENST00000706887.1:c.-88-752T>C

Variant summary

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

The ENST00000706887.1(MADD):​c.-88-752T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 152,092 control chromosomes in the GnomAD database, including 14,780 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 0.42 (14780 hom., cov: 33)
• Consequence: MADD ENST00000706887.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 25 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.-88-752T>C		intron_variant	Intron 1 of 36		NP_001363500.1
MADD	NM_003682.4	c.-88-752T>C		intron_variant	Intron 1 of 35		NP_003673.3
MADD	NM_001376572.1	c.-88-752T>C		intron_variant	Intron 1 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.-88-752T>C		intron_variant	Intron 1 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63720 AN: 151974 Hom.: 14766 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.356

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.419 AC: 63770 AN: 152092 Hom.: 14780 Cov.: 33 AF XY: 0.427 AC XY: 31712 AN XY: 74336

African (AFR) AF: 0.592 AC: 24569 AN: 41496

American (AMR) AF: 0.368 AC: 5628 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3468

East Asian (EAS) AF: 0.693 AC: 3593 AN: 5184

South Asian (SAS) AF: 0.466 AC: 2248 AN: 4822

European-Finnish (FIN) AF: 0.428 AC: 4520 AN: 10550

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21398 AN: 67974

Other (OTH) AF: 0.352 AC: 743 AN: 2112

Alfa AF: 0.425 Hom.: 4770

Bravo AF: 0.421

Asia WGS AF: 0.536 AC: 1860 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.6
DANN	Benign	0.52
PhyloP100		-0.26
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: rs10501321; hg19: chr11-47294626;