dbSNP rs1449626: MADD:c.-164A>C (chr11-47269208-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.122

Publications

16 publications found

Variant links:

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 links:

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]

NR1H3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H3	NM_005693.4 link	c.*512A>C		downstream_gene_variant		ENST00000441012.7	NP_005684.2	Q13133-1B4DXU5F1D8N1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MADD	ENST00000453571.5 link	c.-164A>C	5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000388255.1	C9JM97
MADD	ENST00000342922.8 link	c.-525A>C	upstream_gene_variant		1		ENSP00000343902.4	A0A0A0MRB5
NR1H3	ENST00000441012.7 link	c.*512A>C	downstream_gene_variant		1	NM_005693.4	ENSP00000387946.2	Q13133-1
NR1H3	ENST00000616973.4 link	c.*512A>C	downstream_gene_variant		1		ENSP00000477707.1	B4DXU5

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40221

AN:

152004

Hom.:

6358

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.207

AC XY:

226

AN XY:

1092

show subpopulations

African (AFR)

AF:

0.333

AC:

AN:

American (AMR)

AF:

0.312

AC:

AN:

234

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.429

AC:

AN:

South Asian (SAS)

AF:

0.212

AC:

AN:

260

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.156

AC:

198

AN:

1270

Other (OTH)

AF:

0.258

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.264

AC:

40236

AN:

152122

Hom.:

6361

Cov.:

AF XY:

0.273

AC XY:

20284

AN XY:

74366

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.173

AC:

11780

AN:

67992

Other (OTH)

AF:

0.217

AC:

459

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1454

2908

4361

5815

7269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

408

816

1224

1632

2040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.9

(source)

DANN

Benign

0.60

PhyloP100

0.12

PromoterAI

0.079

Neutral

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over