ENST00000706887.1:c.2251G>C

Variant names:

• chr11-47285034-G-C
• rs1051006
• ENST00000706887.1:c.2251G>C

Variant summary

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

The ENST00000706887.1(MADD):​c.2251G>C​(p.Val751Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MADD ENST00000706887.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.831
• Publications: 60 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=0.02017358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.2251G>C	p.Val751Leu	missense_variant	Exon 13 of 37		NP_001363500.1
MADD	NM_003682.4	c.2251G>C	p.Val751Leu	missense_variant	Exon 13 of 36		NP_003673.3
MADD	NM_001376572.1	c.2251G>C	p.Val751Leu	missense_variant	Exon 13 of 37		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.2251G>C	p.Val751Leu	missense_variant	Exon 13 of 37			ENSP00000516604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251258 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461856 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 12316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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	0.67
DEOGEN2	Benign	0.017	T;.;.;.;T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.020	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.58	.;N;N;N;N;N;N;N;N
PhyloP100		-0.83
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.99	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.51	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.0	.;B;B;B;B;B;.;B;B
Vest4		0.12
MutPred		0.13		Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);Gain of catalytic residue at V751 (P = 0.0592);
MVP		0.067
MPC		0.088
ClinPred		0.013	T
GERP RS		-5.5
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

Other links and lift over

dbSNP: rs1051006; hg19: chr11-47306585;