rs3736101

Variant names:

• chr11-47285077-G-A
• rs3736101
• NM_001376571.1:c.2294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376571.1(MADD):​c.2294G>A​(p.Arg765Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,614,014 control chromosomes in the GnomAD database, including 8,744 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R765W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.077 (520 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8224 hom.)
• Consequence: MADD NM_001376571.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.120
• Publications: 27 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014174283).
• BP6: Variant 11-47285077-G-A is Benign according to our data. Variant chr11-47285077-G-A is described in ClinVar as Benign. ClinVar VariationId is 1321157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.2294G>A	p.Arg765Gln	missense	Exon 13 of 37	NP_001363500.1
	MADD	NM_003682.4		c.2294G>A	p.Arg765Gln	missense	Exon 13 of 36	NP_003673.3
	MADD	NM_001376572.1		c.2294G>A	p.Arg765Gln	missense	Exon 13 of 37	NP_001363501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.2294G>A	p.Arg765Gln	missense	Exon 13 of 37	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.2294G>A	p.Arg765Gln	missense	Exon 13 of 36	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.2294G>A	p.Arg765Gln	missense	Exon 13 of 34	ENSP00000304505.6

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11664 AN: 152010 Hom.: 521 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0841

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0731

GnomAD2 exomes AF: 0.0863 AC: 21692 AN: 251428 AF XY: 0.0893

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.0748

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.0876

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0915

GnomAD4 exome AF: 0.103 AC: 150028 AN: 1461886 Hom.: 8224 Cov.: 33 AF XY: 0.103 AC XY: 74798 AN XY: 727242

African (AFR) AF: 0.0329 AC: 1101 AN: 33480

American (AMR) AF: 0.0373 AC: 1667 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 1979 AN: 26136

East Asian (EAS) AF: 0.0525 AC: 2086 AN: 39700

South Asian (SAS) AF: 0.113 AC: 9724 AN: 86258

European-Finnish (FIN) AF: 0.0932 AC: 4979 AN: 53416

Middle Eastern (MID) AF: 0.0728 AC: 420 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122327 AN: 1112008

Other (OTH) AF: 0.0951 AC: 5745 AN: 60396

GnomAD4 genome AF: 0.0766 AC: 11660 AN: 152128 Hom.: 520 Cov.: 32 AF XY: 0.0754 AC XY: 5610 AN XY: 74384

African (AFR) AF: 0.0354 AC: 1470 AN: 41510

American (AMR) AF: 0.0629 AC: 961 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0775 AC: 269 AN: 3472

East Asian (EAS) AF: 0.0528 AC: 273 AN: 5172

South Asian (SAS) AF: 0.110 AC: 531 AN: 4818

European-Finnish (FIN) AF: 0.0841 AC: 891 AN: 10590

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7062 AN: 67964

Other (OTH) AF: 0.0724 AC: 153 AN: 2114

Alfa AF: 0.0887 Hom.: 1717

Bravo AF: 0.0714

TwinsUK AF: 0.110 AC: 409

ALSPAC AF: 0.113 AC: 437

ESP6500AA AF: 0.0400 AC: 176

ESP6500EA AF: 0.105 AC: 900

ExAC AF: 0.0903 AC: 10970

Asia WGS AF: 0.0770 AC: 267 AN: 3478

EpiCase AF: 0.0994

EpiControl AF: 0.102

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Deeah syndrome (1)
-	-	1	MADD-related disorder (1)
-	-	1	Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.12
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.045
Sift	Benign	0.68	T
Sift4G	Benign	0.29	T
Polyphen		0.0010	B
Vest4		0.22
MPC		0.10
ClinPred		0.0089	T
GERP RS		0.70
Varity_R		0.022
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3736101; hg19: chr11-47306628; COSMIC: COSV60624179; COSMIC: COSV60624179;