chr11-47276809-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001376571.1(MADD):c.1041G>A(p.Glu347Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.64 in 1,613,686 control chromosomes in the GnomAD database, including 338,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 26060 hom., cov: 31)

Exomes 𝑓: 0.65 ( 312698 hom. )

Consequence

MADD
NM_001376571.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.77

Publications

51 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 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

MADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 11-47276809-G-A is Benign according to our data. Variant chr11-47276809-G-A is described in ClinVar as Benign. ClinVar VariationId is 1243998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376571.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MADD	NM_001376571.1	MANE Select	c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 37	NP_001363500.1
MADD	NM_003682.4		c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 36	NP_003673.3
MADD	NM_001376572.1		c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 37	NP_001363501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MADD	ENST00000706887.1	MANE Select	c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 37	ENSP00000516604.1
MADD	ENST00000311027.9	TSL:1	c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 36	ENSP00000310933.4
MADD	ENST00000349238.7	TSL:1	c.1041G>A	p.Glu347Glu	synonymous	Exon 5 of 34	ENSP00000304505.6

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85830

AN:

151888

Hom.:

26041

Cov.:

show subpopulations

Gnomad AFR

AF:

0.356

Gnomad AMI

AF:

0.826

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.756

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.684

Gnomad OTH

AF:

0.632

GnomAD2 exomes

AF:

0.593

AC:

149049

AN:

251424

AF XY:

0.603

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.763

Gnomad EAS exome

AF:

0.294

Gnomad FIN exome

AF:

0.578

Gnomad NFE exome

AF:

0.688

Gnomad OTH exome

AF:

0.666

GnomAD4 exome

AF:

0.647

AC:

946136

AN:

1461680

Hom.:

312698

Cov.:

AF XY:

0.647

AC XY:

470119

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.356

AC:

11903

AN:

33480

American (AMR)

AF:

0.562

AC:

25153

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.763

AC:

19936

AN:

26130

East Asian (EAS)

AF:

0.307

AC:

12192

AN:

39696

South Asian (SAS)

AF:

0.537

AC:

46324

AN:

86244

European-Finnish (FIN)

AF:

0.588

AC:

31386

AN:

53382

Middle Eastern (MID)

AF:

0.708

AC:

4086

AN:

5768

European-Non Finnish (NFE)

AF:

0.680

AC:

756614

AN:

1111870

Other (OTH)

AF:

0.638

AC:

38542

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

16541

33082

49622

66163

82704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19096

38192

57288

76384

95480

<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:

0.565

AC:

85898

AN:

152006

Hom.:

26060

Cov.:

AF XY:

0.559

AC XY:

41494

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.357

AC:

14782

AN:

41440

American (AMR)

AF:

0.624

AC:

9521

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.756

AC:

2622

AN:

3468

East Asian (EAS)

AF:

0.307

AC:

1591

AN:

5182

South Asian (SAS)

AF:

0.533

AC:

2562

AN:

4808

European-Finnish (FIN)

AF:

0.571

AC:

6025

AN:

10560

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.684

AC:

46492

AN:

67962

Other (OTH)

AF:

0.636

AC:

1342

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1732

3464

5196

6928

8660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.649

Hom.:

99743

Bravo

AF:

0.561

Asia WGS

AF:

0.459

AC:

1600

AN:

3478

EpiCase

AF:

0.707

EpiControl

AF:

0.712

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Deeah syndrome

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.2

(source)

DANN

Benign

0.80

PhyloP100

4.8

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over