rs1555685038

Variant names:

• chr18-51047255-A-C
• rs1555685038
• NM_005359.6:c.209A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-51047255-A-C
• chr18-51047255-A-G
• chr18-51047255-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005359.6(SMAD4):​c.209A>C​(p.Lys70Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K70R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.32
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.209A>C	p.Lys70Thr	missense_variant	Exon 2 of 12	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.209A>C	p.Lys70Thr	missense_variant	Exon 2 of 12	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.*232A>C		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000465737.1
ENSG00000267699	ENST00000590722.2	n.*232A>C		3_prime_UTR_variant	Exon 3 of 9	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K70T variant (also known as c.209A>C), located in coding exon 1 of the SMAD4 gene, results from an A to C substitution at nucleotide position 209. The lysine at codon 70 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with threonine at codon 70 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. -

Juvenile polyposis syndrome Uncertain:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 70 of the SMAD4 protein (p.Lys70Thr). This variant is not present in population databases (gnomAD no frequency). 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: 628064). 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. 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;D;D;D;D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;M;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	.;D;.;.;.;D;.;.
REVEL	Uncertain	0.60
Sift	Benign	0.057	.;T;.;.;.;T;.;.
Sift4G	Uncertain	0.035	D;D;D;T;T;D;D;D
Polyphen		0.063	.;B;.;.;.;B;.;.
Vest4		0.85, 0.85, 0.86
MutPred		0.56		Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);Loss of methylation at K70 (P = 4e-04);
MVP		0.94
MPC		2.0
ClinPred		0.98	D
GERP RS		5.6
PromoterAI		-0.0069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.89
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs1555685038; hg19: chr18-48573625; COSMIC: COSV61684449; COSMIC: COSV61684449;