MADD p.Val751Leu

Variant names:

• chr11-47285034-G-T
• NM_001376571.1:c.2251G>T
• MADD p.Val751Leu

Your query was ambiguous. Multiple possible variants found:

• chr11-47285034-G-T
• chr11-47285034-G-C
• chr11-47285034-GTG-TTA
• chr11-47285034-GTG-CTT
• chr11-47285034-GTG-CTC
• chr11-47285034-GTG-CTA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376571.1(MADD):​c.2251G>T​(p.Val751Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V751M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MADD NM_001376571.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.831
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019946009).

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.2251G>T	p.Val751Leu	missense	Exon 13 of 37	NP_001363500.1	A0A9L9PXF1
	MADD	NM_003682.4		c.2251G>T	p.Val751Leu	missense	Exon 13 of 36	NP_003673.3
	MADD	NM_001376572.1		c.2251G>T	p.Val751Leu	missense	Exon 13 of 37	NP_001363501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.2251G>T	p.Val751Leu	missense	Exon 13 of 37	ENSP00000516604.1	A0A9L9PXF1
	MADD	ENST00000311027.9	TSL:1	c.2251G>T	p.Val751Leu	missense	Exon 13 of 36	ENSP00000310933.4	Q8WXG6-1
	MADD	ENST00000349238.7	TSL:1	c.2251G>T	p.Val751Leu	missense	Exon 13 of 34	ENSP00000304505.6	Q8WXG6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.58	N
PhyloP100		-0.83
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.11
Sift	Benign	0.51	T
Sift4G	Benign	0.81	T
Varity_R		0.036
gMVP		0.28
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-47306585;