rs326217

chr11-47281724-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000706887.1(MADD):c.1440T>C(p.Asn480=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,609,658 control chromosomes in the GnomAD database, including 71,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6496 hom., cov: 32)
  • Exomes 𝑓: 0.30 (65389 hom.)
• Consequence: MADD ENST00000706887.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0140

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-47281724-T-C is Benign according to our data. Variant chr11-47281724-T-C is described in ClinVar as [Benign]. Clinvar id is 1321156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MADD	NM_001376571.1	c.1440T>C	p.Asn480=	synonymous_variant	8/37	ENST00000706887.1
MADD	NR_164835.1	n.1642T>C		non_coding_transcript_exon_variant	8/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MADD	ENST00000706887.1	c.1440T>C	p.Asn480=	synonymous_variant	8/37		NM_001376571.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44159 AN: 151906 Hom.: 6476 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.303 AC: 75931 AN: 250342 Hom.: 11848 AF XY: 0.302 AC XY: 40896 AN XY: 135322

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.273

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.297 AC: 433406 AN: 1457634 Hom.: 65389 Cov.: 34 AF XY: 0.297 AC XY: 215449 AN XY: 724876

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.296

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.291 AC: 44224 AN: 152024 Hom.: 6496 Cov.: 32 AF XY: 0.290 AC XY: 21569 AN XY: 74318

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.329

Alfa AF: 0.307 Hom.: 17254

Bravo AF: 0.300

Asia WGS AF: 0.322 AC: 1121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.2
Dann	Benign	0.39

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: rs326217; hg19: chr11-47303275; COSMIC: COSV60627959; COSMIC: COSV60627959;