rs1051006

Positions:

• chr11-47285034-G-A
• chr11-47285034-G-C

Variant summary

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

The NM_001376571.1(MADD):​c.2251G>A​(p.Val751Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,852 control chromosomes in the GnomAD database, including 41,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5998 hom., cov: 32)
  • Exomes 𝑓: 0.20 (35898 hom.)
• Consequence: MADD NM_001376571.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.831

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=2.0590674E-5).
• BP6: Variant 11-47285034-G-A is Benign according to our data. Variant chr11-47285034-G-A is described in ClinVar as [Benign]. Clinvar id is 1276052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MADD	NM_001376571.1	c.2251G>A	p.Val751Met	missense_variant	13/37		NP_001363500.1
MADD	NM_003682.4	c.2251G>A	p.Val751Met	missense_variant	13/36		NP_003673.3
MADD	NM_001376572.1	c.2251G>A	p.Val751Met	missense_variant	13/37		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.2251G>A	p.Val751Met	missense_variant	13/37			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39252 AN: 151880 Hom.: 5997 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.259 AC: 65051 AN: 251258 Hom.: 10890 AF XY: 0.246 AC XY: 33478 AN XY: 135818

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.616

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.203 AC: 296050 AN: 1461854 Hom.: 35898 Cov.: 35 AF XY: 0.202 AC XY: 146574 AN XY: 727218

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.372

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.604

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.258 AC: 39267 AN: 151998 Hom.: 5998 Cov.: 32 AF XY: 0.267 AC XY: 19835 AN XY: 74276

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.215

Alfa AF: 0.183 Hom.: 7736

Bravo AF: 0.264

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.177 AC: 681

ESP6500AA AF: 0.345 AC: 1517

ESP6500EA AF: 0.164 AC: 1414

ExAC AF: 0.249 AC: 30218

Asia WGS AF: 0.324 AC: 1124 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T;.;.;.;T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.000021	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.12	.;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T;T
Polyphen		0.19, 0.062, 0.0020, 0.0030, 0.0060	.;B;B;B;B;B;.;B;B
Vest4		0.097
MPC		0.090
ClinPred		0.0026	T
GERP RS		-5.5
Varity_R		0.029
gMVP		0.28

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: rs1051006; hg19: chr11-47306585; COSMIC: COSV60627965; COSMIC: COSV60627965;