rs749067

Variant names:

• chr11-47296606-T-C
• rs749067
• NM_001376571.1:c.3759+551T>C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001376571.1(MADD):c.3759+551T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.262 (AC=39,783) in the gnomAD database across 152,038 control chromosomes, including 6,801 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.383. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6801 hom., cov: 31)
• Consequence: MADD NM_001376571.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 18 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):

• deeah syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

  Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3832 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MADD NM_001376571.1	MANE Select	c.3759+551T>C	intron	Intron 24 of 36	Prot: NP_001363500.1 UniProt:
	MADD NM_003682.4		c.3759+551T>C	intron	Intron 24 of 35	Prot: NP_003673.3
	MADD NM_001376572.1		c.3747+551T>C	intron	Intron 24 of 36	Prot: NP_001363501.1

MADD NM_001376571.1

MANE Select

HGVSc / HGVSpc.3759+551T>C

Exon rankIntron 24 of 36

intron

Prot: NP_001363500.1UniProt: A0A9L9PXF1

MADD NM_003682.4

HGVSc / HGVSpc.3759+551T>C

Exon rankIntron 24 of 35

intron

Prot: NP_003673.3

MADD NM_001376572.1

HGVSc / HGVSpc.3747+551T>C

Exon rankIntron 24 of 36

intron

Prot: NP_001363501.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MADD ENST00000706887.1	MANE Select	c.3759+551T>C	intron	Intron 24 of 36	Prot: ENSP00000516604.1 UniProt:
	MADD ENST00000311027.9	TSL:1	c.3759+551T>C	intron	Intron 24 of 35	Prot: ENSP00000310933.4 UniProt:
	MADD ENST00000349238.7	TSL:1	c.3705+551T>C	intron	Intron 23 of 33	Prot: ENSP00000304505.6 UniProt:

MADD ENST00000706887.1

MANE Select

HGVSc / HGVSpc.3759+551T>C

Exon rankIntron 24 of 36

intron

Prot: ENSP00000516604.1UniProt: A0A9L9PXF1

MADD ENST00000311027.9

TSL:1

HGVSc / HGVSpc.3759+551T>C

Exon rankIntron 24 of 35

intron

Prot: ENSP00000310933.4UniProt: Q8WXG6-1

MADD ENST00000349238.7

TSL:1

HGVSc / HGVSpc.3705+551T>C

Exon rankIntron 23 of 33

intron

Prot: ENSP00000304505.6UniProt: Q8WXG6-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.262	AC:39796	Hom:6805	AN:151920	Cov:31
GnomAD4 genome	AF: 0.262	AC:39783	Hom:6801	AN:152038	Cov:31
TOPMed (Bravo)	AF: 0.247	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.351	AC:97973	Hom:18534	AN:278780	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.309	AC:723	Hom:124	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0294	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.303	AC:91	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.133	AC:464	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0230	AC:163	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.256	AC:45	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0109	AC:1333	Hom:15	AN:122384	Cov:
Turkish Variome	AF: 0.399	AC:617	Hom:120	AN:1546	Cov:
UK10K	AF: 0.387	AC:2924	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0253	AC:227	Hom:4	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.8
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.73
GPN-Star LLR	N/A	-0.43
GPN-Star score	N/A	0.43
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	1.2

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs749067;

hg19: chr11-47318157;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar