rs10838692

Variant names:

• chr11-47323549-T-C
• rs10838692
• NM_001376571.1:c.4378-122T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376571.1(MADD):​c.4378-122T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 919,454 control chromosomes in the GnomAD database, including 67,017 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12568 hom., cov: 32)
  • Exomes 𝑓: 0.36 (54449 hom.)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	NM_001376571.1	MANE Select	c.4378-122T>C		intron	N/A	NP_001363500.1
	MADD	NM_003682.4		c.4378-122T>C		intron	N/A	NP_003673.3
	MADD	NM_001376572.1		c.4366-122T>C		intron	N/A	NP_001363501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000706887.1	MANE Select	c.4378-122T>C		intron	N/A	ENSP00000516604.1
	MADD	ENST00000311027.9	TSL:1	c.4378-122T>C		intron	N/A	ENSP00000310933.4
	MADD	ENST00000349238.7	TSL:1	c.4261-122T>C		intron	N/A	ENSP00000304505.6

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59618 AN: 151916 Hom.: 12569 Cov.: 32

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.364 AC: 279277 AN: 767420 Hom.: 54449 AF XY: 0.365 AC XY: 143131 AN XY: 391728

African (AFR) AF: 0.500 AC: 9533 AN: 19050

American (AMR) AF: 0.410 AC: 9815 AN: 23966

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 4145 AN: 15810

East Asian (EAS) AF: 0.693 AC: 24107 AN: 34802

South Asian (SAS) AF: 0.468 AC: 25490 AN: 54454

European-Finnish (FIN) AF: 0.410 AC: 18890 AN: 46054

Middle Eastern (MID) AF: 0.265 AC: 676 AN: 2550

European-Non Finnish (NFE) AF: 0.325 AC: 173624 AN: 534430

Other (OTH) AF: 0.358 AC: 12997 AN: 36304

GnomAD4 genome AF: 0.392 AC: 59643 AN: 152034 Hom.: 12568 Cov.: 32 AF XY: 0.401 AC XY: 29785 AN XY: 74312

African (AFR) AF: 0.496 AC: 20559 AN: 41442

American (AMR) AF: 0.357 AC: 5464 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 917 AN: 3470

East Asian (EAS) AF: 0.692 AC: 3580 AN: 5170

South Asian (SAS) AF: 0.467 AC: 2248 AN: 4818

European-Finnish (FIN) AF: 0.429 AC: 4531 AN: 10566

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21402 AN: 67956

Other (OTH) AF: 0.336 AC: 711 AN: 2114

Alfa AF: 0.354 Hom.: 6496

Bravo AF: 0.390

Asia WGS AF: 0.531 AC: 1842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.52
PhyloP100		0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs10838692; hg19: chr11-47345100; COSMIC: COSV60623141; COSMIC: COSV60623141;