NM_005359.6:c.464G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_005359.6(SMAD4):c.464G>C(p.Ser155Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,442,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S155N) 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: 6.31

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:

ENSG00000267699 (HGNC:):

ENSG00000267699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2687882).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000277 (4/1442460) while in subpopulation SAS AF = 0.0000466 (4/85848). AF 95% confidence interval is 0.0000159. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6 link	c.464G>C	p.Ser155Thr	missense_variant	Exon 5 of 12	ENST00000342988.8	NP_005350.1	Q13485A0A024R274

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD4	ENST00000342988.8 link	c.464G>C	p.Ser155Thr	missense_variant	Exon 5 of 12	5	NM_005359.6	ENSP00000341551.3	Q13485
ENSG00000267699	ENST00000590722.2 link	n.*640G>C		non_coding_transcript_exon_variant	Exon 8 of 9	2		ENSP00000465737.1	E7EUB6
ENSG00000267699	ENST00000590722.2 link	n.*640G>C		3_prime_UTR_variant	Exon 8 of 9	2		ENSP00000465737.1	E7EUB6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251360

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1442460

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718702

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33118

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.0000466

AC:

AN:

85848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094272

Other (OTH)

AF:

0.00

AC:

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Apr 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S155T variant (also known as c.464G>C), located in coding exon 4 of the SMAD4 gene, results from a G to C substitution at nucleotide position 464. The serine at codon 155 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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 syndrome

Uncertain:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 155 of the SMAD4 protein (p.Ser155Thr). This variant is present in population databases (rs199790852, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 861894). 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) indicates that this missense variant is not expected to disrupt SMAD4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.47

DEOGEN2

Uncertain

0.54

D;D;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

.;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

6.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

N;N;.

REVEL

Uncertain

0.38

Sift

Benign

0.59

T;T;.

Sift4G

Benign

0.58

T;T;T

Polyphen

0.039

B;B;.

Vest4

0.34

MutPred

0.25

Gain of glycosylation at S155 (P = 0.0228);Gain of glycosylation at S155 (P = 0.0228);Gain of glycosylation at S155 (P = 0.0228);

MVP

0.72

MPC

0.43

ClinPred

0.096

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.055

gMVP

0.42

Mutation Taster

=80/20

polymorphism

(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