rs1051006

Variant names:

• chr11-47285034-G-A
• rs1051006
• ENST00000706887.1:c.2251G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-47285034-G-A
• chr11-47285034-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000706887.1(MADD):​c.2251G>A​(p.Val751Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,852 control chromosomes in the GnomAD database, including 41,896 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5998 hom., cov: 32)
  • Exomes 𝑓: 0.20 (35898 hom.)
• Consequence: MADD ENST00000706887.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.831
• Publications: 60 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0590674E-5).
• BP6: Variant 11-47285034-G-A is Benign according to our data. Variant chr11-47285034-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MADD	NM_001376571.1	c.2251G>A	p.Val751Met	missense_variant	Exon 13 of 37		NP_001363500.1
MADD	NM_003682.4	c.2251G>A	p.Val751Met	missense_variant	Exon 13 of 36		NP_003673.3
MADD	NM_001376572.1	c.2251G>A	p.Val751Met	missense_variant	Exon 13 of 37		NP_001363501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MADD	ENST00000706887.1	c.2251G>A	p.Val751Met	missense_variant	Exon 13 of 37			ENSP00000516604.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39252 AN: 151880 Hom.: 5997 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.259 AC: 65051 AN: 251258 AF XY: 0.246

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.616

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.203 AC: 296050 AN: 1461854 Hom.: 35898 Cov.: 35 AF XY: 0.202 AC XY: 146574 AN XY: 727218

African (AFR) AF: 0.357 AC: 11937 AN: 33480

American (AMR) AF: 0.372 AC: 16622 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3805 AN: 26136

East Asian (EAS) AF: 0.604 AC: 23983 AN: 39700

South Asian (SAS) AF: 0.236 AC: 20360 AN: 86258

European-Finnish (FIN) AF: 0.269 AC: 14347 AN: 53382

Middle Eastern (MID) AF: 0.159 AC: 919 AN: 5768

European-Non Finnish (NFE) AF: 0.172 AC: 191521 AN: 1112010

Other (OTH) AF: 0.208 AC: 12556 AN: 60396

GnomAD4 genome AF: 0.258 AC: 39267 AN: 151998 Hom.: 5998 Cov.: 32 AF XY: 0.267 AC XY: 19835 AN XY: 74276

African (AFR) AF: 0.359 AC: 14888 AN: 41432

American (AMR) AF: 0.273 AC: 4167 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 512 AN: 3472

East Asian (EAS) AF: 0.594 AC: 3060 AN: 5150

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4822

European-Finnish (FIN) AF: 0.297 AC: 3137 AN: 10552

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

European-Non Finnish (NFE) AF: 0.173 AC: 11749 AN: 67976

Other (OTH) AF: 0.215 AC: 454 AN: 2110

Alfa AF: 0.196 Hom.: 12316

Bravo AF: 0.264

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.177 AC: 681

ESP6500AA AF: 0.345 AC: 1517

ESP6500EA AF: 0.164 AC: 1414

ExAC AF: 0.249 AC: 30218

Asia WGS AF: 0.324 AC: 1124 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T;.;.;.;T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.000021	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.12	.;N;N;N;N;N;N;N;N
PhyloP100		-0.83
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T;T
Polyphen		0.19, 0.062, 0.0020, 0.0030, 0.0060	.;B;B;B;B;B;.;B;B
Vest4		0.097
MPC		0.090
ClinPred		0.0026	T
GERP RS		-5.5
Varity_R		0.029
gMVP		0.28
Mutation Taster		=99/1	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: rs1051006; hg19: chr11-47306585; COSMIC: COSV60627965; COSMIC: COSV60627965;