rs3736101

Positions:

• chr11-47285077-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000706887.1(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. 13/20 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 ENST00000706887.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.120

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.2294G>A	p.Arg765Gln	missense_variant	13/37	ENST00000706887.1
MADD	NR_164835.1	n.2496G>A		non_coding_transcript_exon_variant	13/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.2294G>A	p.Arg765Gln	missense_variant	13/37		NM_001376571.1

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

GnomAD3 exomes AF: 0.0863 AC: 21692 AN: 251428 Hom.: 1093 AF XY: 0.0893 AC XY: 12136 AN XY: 135894

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 SAS exome AF: 0.113

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

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.0373

Gnomad4 ASJ exome AF: 0.0757

Gnomad4 EAS exome AF: 0.0525

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.0951

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

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.0629

Gnomad4 ASJ AF: 0.0775

Gnomad4 EAS AF: 0.0528

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.0841

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0946 Hom.: 1425

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deeah syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

MADD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.080	N;N;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.68	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0010, 0.0, 0.0050	.;B;B;B;B
Vest4		0.22
MPC		0.10
ClinPred		0.0089	T
GERP RS		0.70
Varity_R		0.022
gMVP		0.16

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