11-47274810-C-G

Variant names:

• chr11-47274810-C-G
• rs766120355
• NM_001376571.1:c.310C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001376571.1(MADD):​c.310C>G​(p.Arg104Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MADD NM_001376571.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90
• 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: G2P, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32792988).

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.310C>G	p.Arg104Gly	missense	Exon 3 of 37	NP_001363500.1	A0A9L9PXF1
	MADD	NM_003682.4		c.310C>G	p.Arg104Gly	missense	Exon 3 of 36	NP_003673.3
	MADD	NM_001376572.1		c.310C>G	p.Arg104Gly	missense	Exon 3 of 37	NP_001363501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.310C>G	p.Arg104Gly	missense	Exon 3 of 37	ENSP00000516604.1	A0A9L9PXF1
	MADD	ENST00000311027.9	TSL:1	c.310C>G	p.Arg104Gly	missense	Exon 3 of 36	ENSP00000310933.4	Q8WXG6-1
	MADD	ENST00000349238.7	TSL:1	c.310C>G	p.Arg104Gly	missense	Exon 3 of 34	ENSP00000304505.6	Q8WXG6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

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: 53406

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.0012
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Benign	0.095	T
Sift4G	Benign	0.27	T
Polyphen		0.0040	B
Vest4		0.69
MutPred		0.43		Loss of helix (P = 0.0068)
MVP		0.27
MPC		0.45
ClinPred		0.86	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.34
Mutation Taster		=63/37	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: rs766120355; hg19: chr11-47296361;