NM_005359.6:c.829A>G

Variant names:

• chr18-51058381-A-G
• rs1555685960
• NM_005359.6:c.829A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_005359.6(SMAD4):​c.829A>G​(p.Thr277Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. T277I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.19
• Publications: 0 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: 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

ENSG00000267699 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2677548).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.829A>G	p.Thr277Ala	missense	Exon 7 of 12	NP_005350.1
	SMAD4	NM_001407041.1		c.829A>G	p.Thr277Ala	missense	Exon 7 of 12	NP_001393970.1
	SMAD4	NM_001407042.1		c.829A>G	p.Thr277Ala	missense	Exon 7 of 12	NP_001393971.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.829A>G	p.Thr277Ala	missense	Exon 7 of 12	ENSP00000341551.3
	SMAD4	ENST00000591126.5	TSL:1	n.2830A>G		non_coding_transcript_exon	Exon 3 of 8
	SMAD4	ENST00000714264.1		c.829A>G	p.Thr277Ala	missense	Exon 7 of 12	ENSP00000519545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112010

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

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T277A variant (also known as c.829A>G), located in coding exon 6 of the SMAD4 gene, results from an A to G substitution at nucleotide position 829. The threonine at codon 277 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided Uncertain:1

Dec 29, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant summary: The SMAD4 c.829A>G (p.Thr277Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121412 control chromosomes and has not been reported in any patients. Multiple functional studies have shown that Thr277 was located in the linker domain and phosphorylated by ERK and GSK3 (Roelen_2003, Demagny_2014). T277A causes loss of phosphorylation and decrease of the TGF-beta/SMAD4 pathway activity (Roelen_2003). All genes associated with a phenotype of HHT (Hereditary Hemorrahagic Telangectasia), which includes SMAD4, are known to be part of the TGF-beta signaling pathway, while SMAD4 also acts as a tumor suppressor in context of the JPC (Juvenile polyposis coli) phenotype. Mutations in several other genes within this pathway, are also known to cause familial thoracic aneurisms and aortic dissections. Taken together, this variant is classified as a variant of uncertain clinical significance (VUS) unless additional clinical and functional information to unequivocally establish its outcome are obtained.

Juvenile polyposis syndrome Uncertain:1

Feb 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 496291). This sequence change replaces threonine with alanine at codon 277 of the SMAD4 protein (p.Thr277Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMAD4 protein function. 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.0049
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Benign	0.29	T
Sift4G	Benign	0.22	T
Polyphen		0.13	B
Vest4		0.27
MutPred		0.12		Loss of glycosylation at T277 (P = 0.0076)
MVP		0.62
MPC		0.45
ClinPred		0.52	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.65
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555685960; hg19: chr18-48584751;