18-51078294-C-T

Variant names:

• chr18-51078294-C-T
• rs397518413
• NM_005359.6:c.1486C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 18P and 4B. PS3 PM1 PP3_Strong PP5_Very_Strong BS2

The NM_005359.6(SMAD4):​c.1486C>T​(p.Arg496Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001365604: in vitro functional studies (Piccolo 2014, Li 2020) provide evidence that the p.Arg496Cys variant may impact protein function.; SCV002767131: Functional analysis on missense variants shows both gain of function and dominant negative effects at the same residue (PMIDs: 22158539, 36194927); SCV000211671: Published functional studies demonstrate a damaging effect showing elevated SMAD4 levels and impaired microfibril deposition causing an extracellular matrix defect (Piccolo et al., 2014); PMID:24424121, 24398790, 24715504, 27302097, 28051901, 24841914, 24580733, 28867141, 31654632, 31595668, 31837202, 31447099, 33428109, 30787465, 31785789, 17873119, 18823382, 15235019; SCV005878823: Functional analysis of the variant protein showed increased protein levels and impaired function (Li 2020, Piccolo 2014). PMID:31654632. PMID:24398790.; SCV000672002: Functional consequences of this alteration have been investigated; skin fibroblasts exhibited increased SMAD4 proteins compared with wildtype controls which only showed detectable SMAD4 protein following TGF-β stimulation, increased phosphorylated SMAD2 proteins, matrix metalloproteinase (MMP) overexpression, and impaired microfibril deposition within the extracellular domain (Piccolo, 2014).; SCV004110014: Functional in vitro studies showed an increase in SMAD4 protein in fibroblasts with the p.Arg496Cys variant and altered expression of downstream transcriptional target genes (Piccolo et al. 2014. PubMed ID: 24398790).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:2
• Conservation: PhyloP100: 7.75
• Publications: 33 publications found

Genes affected

SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

SMAD4 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001365604: in vitro functional studies (Piccolo 2014, Li 2020) provide evidence that the p.Arg496Cys variant may impact protein function.; SCV002767131: Functional analysis on missense variants shows both gain of function and dominant negative effects at the same residue (PMIDs: 22158539, 36194927); SCV000211671: Published functional studies demonstrate a damaging effect showing elevated SMAD4 levels and impaired microfibril deposition causing an extracellular matrix defect (Piccolo et al., 2014); PMID: 24424121, 24398790, 24715504, 27302097, 28051901, 24841914, 24580733, 28867141, 31654632, 31595668, 31837202, 31447099, 33428109, 30787465, 31785789, 17873119, 18823382, 15235019; SCV005878823: Functional analysis of the variant protein showed increased protein levels and impaired function (Li 2020, Piccolo 2014). PMID: 31654632. PMID: 24398790.; SCV000672002: Functional consequences of this alteration have been investigated; skin fibroblasts exhibited increased SMAD4 proteins compared with wildtype controls which only showed detectable SMAD4 protein following TGF-β stimulation, increased phosphorylated SMAD2 proteins, matrix metalloproteinase (MMP) overexpression, and impaired microfibril deposition within the extracellular domain (Piccolo, 2014).; SCV004110014: Functional in vitro studies showed an increase in SMAD4 protein in fibroblasts with the p.Arg496Cys variant and altered expression of downstream transcriptional target genes (Piccolo et al. 2014. PubMed ID: 24398790).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_005359.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 18-51078294-C-T is Pathogenic according to our data. Variant chr18-51078294-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005359.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.1486C>T	p.Arg496Cys	missense	Exon 12 of 12	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.1486C>T	p.Arg496Cys	missense	Exon 12 of 12	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.1486C>T	p.Arg496Cys	missense	Exon 12 of 12	NP_001393971.1	Q13485

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.1486C>T	p.Arg496Cys	missense	Exon 12 of 12	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3487C>T		non_coding_transcript_exon	Exon 8 of 8
	SMAD4	ENST00000714264.1		c.1567C>T	p.Arg523Cys	missense	Exon 12 of 12	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251432 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Myhre syndrome (12)
10	-	-	not provided (10)
2	-	-	SMAD4-related disorder (2)
1	-	-	Carcinoma of pancreas;C0345893:Juvenile polyposis syndrome;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1)
1	-	-	Generalized juvenile polyposis/juvenile polyposis coli (1)
1	-	-	Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Intellectual disability (1)
1	-	-	Juvenile polyposis syndrome (1)
1	-	-	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1)
1	-	-	Moyamoya angiopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.71		Loss of helix (P = 0.0558)
MVP		0.98
MPC		3.4
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.95
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397518413; hg19: chr18-48604664; COSMIC: COSV61684064;