18-51078442-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_005359.6(SMAD4):c.1634T>C(p.Ile545Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I545N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD4
NM_005359.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.15

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
Myhre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
generalized juvenile polyposis/juvenile polyposis coli
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
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

SMAD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a domain MH2 (size 229) in uniprot entity SMAD4_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) in NM_005359.6

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD4	NM_005359.6	MANE Select	c.1634T>C	p.Ile545Thr	missense	Exon 12 of 12	NP_005350.1
SMAD4	NM_001407041.1		c.1634T>C	p.Ile545Thr	missense	Exon 12 of 12	NP_001393970.1
SMAD4	NM_001407042.1		c.1634T>C	p.Ile545Thr	missense	Exon 12 of 12	NP_001393971.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.1634T>C	p.Ile545Thr	missense	Exon 12 of 12	ENSP00000341551.3
SMAD4	ENST00000591126.5	TSL:1	n.3635T>C		non_coding_transcript_exon	Exon 8 of 8
SMAD4	ENST00000714264.1		c.1715T>C	p.Ile572Thr	missense	Exon 12 of 12	ENSP00000519545.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

May 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I545T variant (also known as c.1634T>C), located in coding exon 11 of the SMAD4 gene, results from a T to C substitution at nucleotide position 1634. The isoleucine at codon 545 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Uncertain:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces isoleucine with threonine at codon 545 of the SMAD4 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.7

PhyloP100

6.2

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.50

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0090

Polyphen

0.15

Vest4

0.45

MutPred

0.34

Gain of glycosylation at I545 (P = 0.0044)

MVP

0.93

MPC

1.9

ClinPred

0.89

GERP RS

6.0

Varity_R

0.63

gMVP

0.77

Mutation Taster

=9/91

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over