18-51067174-G-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.1295G>C(p.Ser432Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,429,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S432N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SMAD4
NM_005359.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.82

Publications

2 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMAD4	NM_005359.6 link	c.1295G>C	p.Ser432Thr	missense_variant	Exon 10 of 12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1 link	c.1295G>C	p.Ser432Thr	missense_variant	Exon 10 of 12		NP_001393970.1
SMAD4	NM_001407042.1 link	c.1295G>C	p.Ser432Thr	missense_variant	Exon 10 of 12		NP_001393971.1
SMAD4	NR_176265.1 link	n.1833G>C		non_coding_transcript_exon_variant	Exon 10 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8 link	c.1295G>C	p.Ser432Thr	missense_variant	Exon 10 of 12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251396

AF XY:

0.00000736

show subpopulations

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1429140

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

713096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32842

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

85524

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082262

Other (OTH)

AF:

0.00

AC:

AN:

59312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Jul 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S432T variant (also known as c.1295G>C), located in coding exon 9 of the SMAD4 gene, results from a G to C substitution at nucleotide position 1295. The serine at codon 432 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Uncertain:1

Apr 03, 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 serine with threonine at codon 432 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 been identified in 1/251396 chromosomes 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

D;D;D;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.0

.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.61

D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.5

L;L;.;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N;.;.

REVEL

Uncertain

0.57

Sift

Benign

0.069

T;T;.;.

Sift4G

Benign

0.071

T;T;D;T

Vest4

0.57

ClinPred

0.58

GERP RS

5.2

PromoterAI

0.0062

Neutral

(source)

Varity_R

0.60

gMVP

0.88

Mutation Taster

=34/66

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over