NM_001376651.1:c.-164A>C

Variant names:

• chr11-47269208-A-C
• rs1449626
• NM_001376651.1:c.-164A>C

Variant summary

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

The NM_001376651.1(MADD):​c.-164A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 153,988 control chromosomes in the GnomAD database, including 6,402 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 0.26 (6361 hom., cov: 32)
  • Exomes 𝑓: 0.19 (41 hom.)
• Consequence: MADD NM_001376651.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 16 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]

NR1H3 (HGNC:7966): (nuclear receptor subfamily 1 group H member 3) The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376651.1. 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_001376651.1		c.-164A>C		5_prime_UTR	Exon 1 of 33	NP_001363580.1
	NR1H3	NM_005693.4	MANE Select	c.*512A>C		downstream_gene	N/A	NP_005684.2
	MADD	NM_130470.3		c.-525A>C		upstream_gene	N/A	NP_569826.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MADD	ENST00000453571.5	TSL:4	c.-164A>C		5_prime_UTR	Exon 1 of 3	ENSP00000388255.1
	MADD	ENST00000342922.8	TSL:1	c.-525A>C		upstream_gene	N/A	ENSP00000343902.4
	NR1H3	ENST00000441012.7	TSL:1 MANE Select	c.*512A>C		downstream_gene	N/A	ENSP00000387946.2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40221 AN: 152004 Hom.: 6358 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.191 AC: 357 AN: 1866 Hom.: 41 Cov.: 0 AF XY: 0.207 AC XY: 226 AN XY: 1092

African (AFR) AF: 0.333 AC: 2 AN: 6

American (AMR) AF: 0.312 AC: 73 AN: 234

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 4 AN: 8

East Asian (EAS) AF: 0.429 AC: 6 AN: 14

South Asian (SAS) AF: 0.212 AC: 55 AN: 260

European-Finnish (FIN) AF: 0.250 AC: 3 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.156 AC: 198 AN: 1270

Other (OTH) AF: 0.258 AC: 16 AN: 62

GnomAD4 genome AF: 0.264 AC: 40236 AN: 152122 Hom.: 6361 Cov.: 32 AF XY: 0.273 AC XY: 20284 AN XY: 74366

African (AFR) AF: 0.380 AC: 15769 AN: 41486

American (AMR) AF: 0.274 AC: 4185 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3472

East Asian (EAS) AF: 0.597 AC: 3073 AN: 5150

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4824

European-Finnish (FIN) AF: 0.298 AC: 3160 AN: 10588

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11780 AN: 67992

Other (OTH) AF: 0.217 AC: 459 AN: 2112

Alfa AF: 0.242 Hom.: 2543

Bravo AF: 0.270

Asia WGS AF: 0.325 AC: 1129 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.60
PhyloP100		0.12
PromoterAI		0.079	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1449626; hg19: chr11-47290759;