chr18-51065548-C-T

Position:

chr18-51065548-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_005359.6(SMAD4):c.1081C>T(p.Arg361Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R361G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMAD4
NM_005359.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:2

Conservation

PhyloP100: 4.79

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 4) in uniprot entity SMAD4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) 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 chr18-51065548-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ: 4.1308 (greater than the threshold 3.09). Trascript score misZ: 4.9346 (greater than threshold 3.09). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 52 curated benign missense variants. GenCC has associacion of the gene with familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 18-51065548-C-T is Pathogenic according to our data. Variant chr18-51065548-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-51065548-C-T is described in Lovd as [Pathogenic]. Variant chr18-51065548-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6 link	c.1081C>T	p.Arg361Cys	missense_variant	9/12	ENST00000342988.8	NP_005350.1	Q13485A0A024R274

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8 link	c.1081C>T	p.Arg361Cys	missense_variant	9/12	5	NM_005359.6	ENSP00000341551.3		Q13485

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PM2+PM1+PP2+PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 09, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15799969]. This variant is expected to disrupt protein structure [PMID: 9214508]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10764709, 16613914, 20101697, 17873119, 9811934, 15031030]. -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2019	The SMAD4 c.1081C>T; p.Arg361Cys variant (rs80338963) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) or juvenile polyposis syndrome (JPS) (Aretz 2007, Gallione 2006, Gallione 2010, Houlston 1998, Woodford-Richens 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at amino acid 361 is highly conserved, and functional analyses suggest that this variant exhibits deficient homo-oligomerization and deficient binding to other partner proteins (Shi 1997), which may result in instability and degradation (Woodford-Richens 2001). Additionally, other amino acid substitutions at this codon (Gly, His, Leu, Ser) have been reported in individuals with HHT or JPS and are considered disease-causing (Aretz 2007, Gallione 2010, Howe 2004). Based on available information, the p.Arg361Cys variant is considered to be pathogenic. References: Aretz S et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007 Nov;44(11):702-9. Gallione C et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010 Feb;152A(2):333-9. Gallione CJ et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006 Oct;43(10):793-7. Houlston et al. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. Hum Mol Genet. 1998 Nov;7(12):1907-12. Howe JR et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004 Jul;41(7):484-91. Shi Y et al. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997 Jul 3;388(6637):87-93. Woodford-Richens KL et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol. 2001 Oct;159(4):1293-300. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2021	PS4, PM6_strong, PM1, PM5, PM2, PP3 -

Juvenile polyposis syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 361 of the SMAD4 protein (p.Arg361Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with juvenile polyposis syndrome (JPS) and/or hereditary hemorrhagic telangiectasia (HHT) (PMID: 9811934, 10764709, 16613914, 17873119, 20101697). ClinVar contains an entry for this variant (Variation ID: 8543). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 9214508, 11583957). This variant disrupts the p.Arg361 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10797267, 15031030, 15235019, 20101697, 22316667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

SMAD4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The SMAD4 c.1081C>T variant is predicted to result in the amino acid substitution p.Arg361Cys. This variant has been reported in multiple individuals with juvenile polyposis coli and hereditary hemorrhagic telangiectasia syndrome (see for example, Table 1, Woodford-Richens et al. 2000. PubMed ID: 10764709; Table 1, Gallione et al. 2010. PubMed ID: 20101697; Hashimoto et al. 2020. PubMed ID: 32944796). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8543/). Alternate nucleotide substitutions affecting the same amino acid (p.Arg361His, p.Arg361Gly, p.Arg361Leu, and p.Arg361Ser), have been reported in multiple individuals with juvenile polyposis coli and hereditary hemorrhagic telangiectasia syndrome (Table 1, Howe et al. 2004. PubMed ID: 15235019; Table 1, Gallione et al. 2004. PubMed ID: 15031030; Table 1, Gallione et al. 2010. PubMed ID: 20101697). The c.1081C>T (p.Arg361Cys) variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The p.R361C pathogenic mutation (also known as c.1081C>T), located in coding exon 8 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1081. The arginine at codon 361 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple patients with a clinical diagnosis of juvenile polyposis syndrome (JPS) (Houlston R et al. Hum. Mol. Genet. 1998; 7:1907-12, Aretz S et al. J. Med. Genet. 2007; 44:702-9), as well as in multiple patients with combined juvenile polyposis - hereditary hemorrhagic telangiectasia (JP-HHT) syndrome (Gallione C et al. Am. J. Med. Genet. A 2010; 152A:333-9; Jelsig AM et al. Clin Genet. 2016 Jul;90(1):55-62). This alteration has also been reported in a hereditary hemorrhagic telangiectasia (HHT) cohort (Shovlin CL et al. Blood, 2020 10;136:1907-1918). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Multiple other alterations at this same codon (p.R361G, p.R361H, p.R361L, p.R361S) have also been described in individuals with clinical JPS. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Generalized juvenile polyposis/juvenile polyposis coli

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.8

D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.99

Loss of solvent accessibility (P = 0.0404);Loss of solvent accessibility (P = 0.0404);.;

MVP

1.0

MPC

3.4

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over