rs326217

Variant names:

• chr11-47281724-T-C
• rs326217
• NM_001376571.1:c.1440T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001376571.1(MADD):​c.1440T>C​(p.Asn480Asn) 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 NM_001376571.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0140
• Publications: 53 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 -21 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 VariationId is 1321156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 37	NP_001363500.1
	MADD	NM_003682.4		c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 36	NP_003673.3
	MADD	NM_001376572.1		c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 37	NP_001363501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 37	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 36	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.1440T>C	p.Asn480Asn	synonymous	Exon 8 of 34	ENSP00000304505.6

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

GnomAD2 exomes AF: 0.303 AC: 75931 AN: 250342 AF XY: 0.302

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 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

African (AFR) AF: 0.252 AC: 8430 AN: 33398

American (AMR) AF: 0.379 AC: 16923 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 9800 AN: 26044

East Asian (EAS) AF: 0.289 AC: 11455 AN: 39602

South Asian (SAS) AF: 0.277 AC: 23791 AN: 85928

European-Finnish (FIN) AF: 0.274 AC: 14607 AN: 53312

Middle Eastern (MID) AF: 0.348 AC: 2000 AN: 5750

European-Non Finnish (NFE) AF: 0.296 AC: 327698 AN: 1108824

Other (OTH) AF: 0.311 AC: 18702 AN: 60182

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

African (AFR) AF: 0.246 AC: 10184 AN: 41456

American (AMR) AF: 0.373 AC: 5691 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1299 AN: 3470

East Asian (EAS) AF: 0.286 AC: 1482 AN: 5174

South Asian (SAS) AF: 0.282 AC: 1359 AN: 4818

European-Finnish (FIN) AF: 0.260 AC: 2740 AN: 10554

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20244 AN: 67976

Other (OTH) AF: 0.329 AC: 695 AN: 2112

Alfa AF: 0.302 Hom.: 33227

Bravo AF: 0.300

Asia WGS AF: 0.322 AC: 1121 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Deeah syndrome (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
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.2
DANN	Benign	0.39
PhyloP100		-0.014
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

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