rs753993

Variant names:

• chr11-47328418-C-A
• rs753993
• ENST00000469699.1:n.277C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-47328418-C-A
• chr11-47328418-C-G
• chr11-47328418-C-T

Variant summary

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

The ENST00000469699.1(MADD):​n.277C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,419,240 control chromosomes in the GnomAD database, including 51,719 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 0.33 (10052 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41667 hom.)
• Consequence: MADD ENST00000469699.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.104
• Publications: 15 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4802-240C>A		intron_variant	Intron 35 of 36		NP_001363500.1
MADD	NM_003682.4	c.4793-240C>A		intron_variant	Intron 34 of 35		NP_003673.3
MADD	NM_001376572.1	c.4790-240C>A		intron_variant	Intron 35 of 36		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.4802-240C>A		intron_variant	Intron 35 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50420 AN: 151912 Hom.: 10045 Cov.: 33

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.238 AC: 302030 AN: 1267206 Hom.: 41667 Cov.: 32 AF XY: 0.240 AC XY: 147205 AN XY: 613632

African (AFR) AF: 0.526 AC: 14645 AN: 27842

American (AMR) AF: 0.345 AC: 6504 AN: 18860

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 3461 AN: 18408

East Asian (EAS) AF: 0.637 AC: 21426 AN: 33648

South Asian (SAS) AF: 0.342 AC: 20741 AN: 60664

European-Finnish (FIN) AF: 0.304 AC: 8773 AN: 28892

Middle Eastern (MID) AF: 0.197 AC: 755 AN: 3828

European-Non Finnish (NFE) AF: 0.207 AC: 212138 AN: 1022674

Other (OTH) AF: 0.259 AC: 13587 AN: 52390

GnomAD4 genome AF: 0.332 AC: 50457 AN: 152034 Hom.: 10052 Cov.: 33 AF XY: 0.340 AC XY: 25252 AN XY: 74298

African (AFR) AF: 0.521 AC: 21607 AN: 41474

American (AMR) AF: 0.303 AC: 4630 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3468

East Asian (EAS) AF: 0.634 AC: 3256 AN: 5132

South Asian (SAS) AF: 0.346 AC: 1668 AN: 4824

European-Finnish (FIN) AF: 0.344 AC: 3632 AN: 10560

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14251 AN: 67976

Other (OTH) AF: 0.270 AC: 570 AN: 2108

Alfa AF: 0.379 Hom.: 2835

Bravo AF: 0.339

Asia WGS AF: 0.450 AC: 1564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.8
DANN	Benign	0.86
PhyloP100		0.10
Mutation Taster		=100/0	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: rs753993; hg19: chr11-47349969;