11-47274882-T-C

Position:

• chr11-47274882-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001376571.1(MADD):​c.382T>C​(p.Ser128Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: MADD NM_001376571.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.413

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05504647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADD	NM_001376571.1	c.382T>C	p.Ser128Pro	missense_variant	3/37		NP_001363500.1
MADD	NM_003682.4	c.382T>C	p.Ser128Pro	missense_variant	3/36		NP_003673.3
MADD	NM_001376572.1	c.382T>C	p.Ser128Pro	missense_variant	3/37		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.382T>C	p.Ser128Pro	missense_variant	3/37			ENSP00000516604.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251068 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461710 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MADD-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2023

The MADD c.382T>C variant is predicted to result in the amino acid substitution p.Ser128Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47296433-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.055	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	.;N;N;N;N;N;N;.;N;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;.;.;B;B;.
Vest4		0.22
MutPred		0.19		Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);Loss of phosphorylation at S128 (P = 0.0092);
MVP		0.15
MPC		0.44
ClinPred		0.013	T
GERP RS		-0.79
Varity_R		0.097
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs763479544; hg19: chr11-47296433;