ENST00000469699.1:n.154G>A

Variant names:

• chr11-47328295-G-A
• rs753992
• ENST00000469699.1:n.154G>A

Variant summary

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

The ENST00000469699.1(MADD):​n.154G>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 0.185 in 1,158,666 control chromosomes in the GnomAD database, including 22,146 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 0.21 (3940 hom., cov: 33)
  • Exomes 𝑓: 0.18 (18206 hom.)
• Consequence: MADD ENST00000469699.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568
• Publications: 17 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.4802-363G>A		intron_variant	Intron 35 of 36		NP_001363500.1
MADD	NM_003682.4	c.4793-363G>A		intron_variant	Intron 34 of 35		NP_003673.3
MADD	NM_001376572.1	c.4790-363G>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.4802-363G>A		intron_variant	Intron 35 of 36			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31941 AN: 151988 Hom.: 3934 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.182 AC: 182724 AN: 1006560 Hom.: 18206 Cov.: 32 AF XY: 0.182 AC XY: 86244 AN XY: 474940

African (AFR) AF: 0.181 AC: 3995 AN: 22074

American (AMR) AF: 0.306 AC: 2373 AN: 7748

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 1772 AN: 10286

East Asian (EAS) AF: 0.567 AC: 7619 AN: 13440

South Asian (SAS) AF: 0.226 AC: 8022 AN: 35552

European-Finnish (FIN) AF: 0.242 AC: 2160 AN: 8922

Middle Eastern (MID) AF: 0.144 AC: 344 AN: 2390

European-Non Finnish (NFE) AF: 0.172 AC: 149175 AN: 868774

Other (OTH) AF: 0.194 AC: 7264 AN: 37374

GnomAD4 genome AF: 0.210 AC: 31947 AN: 152106 Hom.: 3940 Cov.: 33 AF XY: 0.220 AC XY: 16347 AN XY: 74340

African (AFR) AF: 0.195 AC: 8085 AN: 41524

American (AMR) AF: 0.254 AC: 3878 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 602 AN: 3472

East Asian (EAS) AF: 0.570 AC: 2938 AN: 5156

South Asian (SAS) AF: 0.231 AC: 1114 AN: 4822

European-Finnish (FIN) AF: 0.299 AC: 3157 AN: 10570

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11661 AN: 67968

Other (OTH) AF: 0.173 AC: 364 AN: 2110

Alfa AF: 0.183 Hom.: 4379

Bravo AF: 0.209

Asia WGS AF: 0.307 AC: 1066 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.72
PhyloP100		0.57
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: rs753992; hg19: chr11-47349846;