rs326214

chr11-47276809-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.1041G>A(p.Glu347=) variant causes a synonymous change. The variant allele was found at a frequency of 0.64 in 1,613,686 control chromosomes in the GnomAD database, including 338,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26060 hom., cov: 31)
  • Exomes 𝑓: 0.65 (312698 hom.)
• Consequence: MADD ENST00000706887.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.77

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 (BayesDel_noAF=-0.48).
• BP6: Variant 11-47276809-G-A is Benign according to our data. Variant chr11-47276809-G-A is described in ClinVar as [Benign]. Clinvar id is 1243998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.1041G>A	p.Glu347=	synonymous_variant	5/37	ENST00000706887.1
MADD	NR_164835.1	n.1243G>A		non_coding_transcript_exon_variant	5/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.1041G>A	p.Glu347=	synonymous_variant	5/37		NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85830 AN: 151888 Hom.: 26041 Cov.: 31

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.826

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.756

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.632

GnomAD3 exomes AF: 0.593 AC: 149049 AN: 251424 Hom.: 46527 AF XY: 0.603 AC XY: 81930 AN XY: 135888

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.294

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.647 AC: 946136 AN: 1461680 Hom.: 312698 Cov.: 50 AF XY: 0.647 AC XY: 470119 AN XY: 727166

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.562

Gnomad4 ASJ exome AF: 0.763

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.680

Gnomad4 OTH exome AF: 0.638

GnomAD4 genome AF: 0.565 AC: 85898 AN: 152006 Hom.: 26060 Cov.: 31 AF XY: 0.559 AC XY: 41494 AN XY: 74284

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.756

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.684

Gnomad4 OTH AF: 0.636

Alfa AF: 0.671 Hom.: 73127

Bravo AF: 0.561

Asia WGS AF: 0.459 AC: 1600 AN: 3478

EpiCase AF: 0.707

EpiControl AF: 0.712

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

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.2
Dann	Benign	0.80

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: rs326214; hg19: chr11-47298360; COSMIC: COSV60628604; COSMIC: COSV60628604;