11-47274581-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000706887.1(MADD):c.81C>A(p.Ser27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MADD ENST00000706887.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.679

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27115017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.81C>A	p.Ser27Arg	missense_variant	3/37	ENST00000706887.1
MADD	NR_164835.1	n.283C>A		non_coding_transcript_exon_variant	3/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.81C>A	p.Ser27Arg	missense_variant	3/37		NM_001376571.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460020 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725942

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Apr 18, 2023

The c.81C>A (p.S27R) alteration is located in exon 3 (coding exon 2) of the MADD gene. This alteration results from a C to A substitution at nucleotide position 81, causing the serine (S) at amino acid position 27 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.014	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;T;T;T;T;T;T;T;D;T;T;D
Polyphen		1.0, 0.75, 1.0, 0.99	.;.;D;P;D;D;D;.;.;D;D;.
Vest4		0.59, 0.63, 0.61, 0.67, 0.67, 0.65, 0.64, 0.60, 0.68
MutPred		0.43		Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);Gain of catalytic residue at S27 (P = 0.0524);
MVP		0.16
MPC		1.1
ClinPred		0.99	D
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs746888060; hg19: chr11-47296132;