NM_005359.6:c.1498A>G

Variant names:

• chr18-51078306-A-G
• rs281875322
• NM_005359.6:c.1498A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 PP5_Very_Strong

The NM_005359.6(SMAD4):​c.1498A>G​(p.Ile500Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005397384: "Cultured cells containing this variant had an increased production of SMAD4, an altered pattern of gene expression related to the maintence of the extracelluar matrix, and a disrupted extracellular matrix (PMID:24398790)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I500T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:46 O:2
• Conservation: PhyloP100: 9.17
• Publications: 41 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005397384: "Cultured cells containing this variant had an increased production of SMAD4, an altered pattern of gene expression related to the maintence of the extracelluar matrix, and a disrupted extracellular matrix (PMID: 24398790)."; SCV005416697: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006586830: Functional studies show compromised activation of the TGF-β pathway, consistent with a dominant-negative mechanism associated with Myhre syndrome (PMID: 36194927).; SCV000211666: Published functional studies demonstrate a damaging effect as p.(I500V) resulted in dysregulation of both matrix metalloproteinases and related inhibitors (Piccolo et al., 2014); PMID: 26633542; SCV003802792: The valine and threonine changes have been shown to disrupt TGF-β and BMP signaling in HEK293T cells and patient fibroblasts, and the p.Ile500Val variant has been specifically shown to have a dominant-negative effect on wild-type SMAD4 (PMID: 22158539; PMID 36194927).; SCV000840072: Functional studies on this variant suggested increased SMAD4 protein levels and increased TGF-beta signaling (PMID 24398790).; SCV001423686: "supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing" [PS3]; SCV000756840: Experimental studies have shown that this missense change affects SMAD4 function (PMID: 24398790).; SCV002061175: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID 24398790) - PS3."; SCV000741420: Functional analysis demonstrated that the p.I500V alteration interferes with ubiquitination and degradation of SMAD4 resulting in accumulation of protein and induction of the TGFbeta pathway (Le Goff, 2011; Caputo, 2012; Piccolo, 2014).; SCV005362938: "In vitro experimental studies suggest this variant affects protein function (Piccolo et al. 2014. PubMed ID: 24398790)."; SCV006557300: Experiments using p.Ile500Val patient fibroblasts have shown a disruption of TGF-B and BMP signaling.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-51078307-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 18-51078306-A-G is Pathogenic according to our data. Variant chr18-51078306-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1498A>G	p.Ile500Val	missense	Exon 12 of 12	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.1498A>G	p.Ile500Val	missense	Exon 12 of 12	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.1498A>G	p.Ile500Val	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.1498A>G	p.Ile500Val	missense	Exon 12 of 12	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3499A>G		non_coding_transcript_exon	Exon 8 of 8
	SMAD4	ENST00000714264.1		c.1579A>G	p.Ile527Val	missense	Exon 12 of 12	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 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: 8.99e-7 AC: 1 AN: 1112006

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
21	-	-	Myhre syndrome (22)
12	-	-	not provided (13)
2	-	-	Juvenile polyposis syndrome (2)
2	-	-	SMAD4-related disorder (2)
1	-	-	Carcinoma of pancreas;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;C1868081:Generalized juvenile polyposis/juvenile polyposis coli (1)
1	-	-	Familial aortopathy (1)
1	-	-	Familial renal glucosuria (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/hereditary hemorrhagic telangiectasia syndrome (1)
1	-	-	Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;C1868081:Generalized juvenile polyposis/juvenile polyposis coli (1)
1	-	-	Neurodevelopmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.84	N
REVEL	Pathogenic	0.71
Sift	Benign	0.041	D
Sift4G	Benign	0.59	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.52		Gain of catalytic residue at I500 (P = 0.0315)
MVP		0.94
MPC		2.2
ClinPred		0.71	D
GERP RS		6.1
Varity_R		0.49
gMVP		0.70
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281875322; hg19: chr18-48604676;