11-47274706-T-G

Position:

• chr11-47274706-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001376620.1(MADD):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: MADD NM_001376620.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADD	NM_001376620.1	c.2T>G	p.Met1?	start_lost	2/33		NP_001363549.1
MADD	NM_001376626.1	c.2T>G	p.Met1?	start_lost	2/34		NP_001363555.1
MADD	NM_001376627.1	c.2T>G	p.Met1?	start_lost	2/36		NP_001363556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.206T>G	p.Met69Arg	missense_variant	3/37			ENSP00000516604.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.206T>G (p.M69R) alteration is located in exon 3 (coding exon 2) of the MADD gene. This alteration results from a T to G substitution at nucleotide position 206, causing the methionine (M) at amino acid position 69 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.084	T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.90	.;.;L;L;L;L;L;L;.;L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.15	T;T;D;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.013	D;T;T;T;T;T;T;T;D;T;T;D
Polyphen		0.039, 0.0070, 0.0040, 0.89, 0.73, 0.22	.;.;B;B;B;B;P;.;.;P;B;.
Vest4		0.60, 0.61, 0.62, 0.62, 0.63, 0.60, 0.64, 0.62
MutPred		0.54		Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);Gain of disorder (P = 0.0306);
MVP		0.22
MPC		0.81
ClinPred		0.85	D
GERP RS		3.9
Varity_R		0.42
gMVP		0.51

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47296257;