11-47274631-C-A

Position:

chr11-47274631-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001376620.1(MADD):c.-74C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,218 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0061 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 12 hom. )

Consequence

MADD
NM_001376620.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.23

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:

MADD (HGNC:):

MADD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004262507).

BP6

Variant 11-47274631-C-A is Benign according to our data. Variant chr11-47274631-C-A is described in ClinVar as [Benign]. Clinvar id is 709997.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00608 (927/152342) while in subpopulation AFR AF= 0.0211 (875/41564). AF 95% confidence interval is 0.0199. There are 13 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	Protein
MADD	NM_001376620.1 linkuse as main transcript	c.-74C>A	5_prime_UTR_premature_start_codon_gain_variant	2/33	NP_001363549.1
MADD	NM_001376626.1 linkuse as main transcript	c.-74C>A	5_prime_UTR_premature_start_codon_gain_variant	2/34	NP_001363555.1
MADD	NM_001376627.1 linkuse as main transcript	c.-74C>A	5_prime_UTR_premature_start_codon_gain_variant	2/36	NP_001363556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1 linkuse as main transcript	c.131C>A	p.Thr44Asn	missense_variant	3/37			ENSP00000516604.1		A0A9L9PXF1

Frequencies

GnomAD3 genomes

AF:

0.00605

AC:

921

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00147

AC:

369

AN:

251440

Hom.:

AF XY:

0.00106

AC XY:

144

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000564

AC:

825

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

338

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0205

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00608

AC:

927

AN:

152342

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

437

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0211

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.00684

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00181

AC:

220

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MADD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.018

T;T;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0043

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;N;N;N;N;N;N;.;N;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.30

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.33

T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.50

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

.;.;B;B;B;B;B;.;.;B;B;.

Vest4

0.21, 0.24, 0.18, 0.20, 0.20, 0.20, 0.16, 0.23

MVP

0.32

MPC

0.40

ClinPred

0.0067

GERP RS

5.1

Varity_R

0.077

gMVP

0.093

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over