rs281875323

Variant names:

• chr18-51047084-A-G
• rs281875323
• NM_005359.6:c.38A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-51047084-A-G
• chr18-51047084-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005359.6(SMAD4):​c.38A>G​(p.Asn13Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,540 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N13D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1 O:2
• Conservation: PhyloP100: 7.43
• Publications: 10 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27581304).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.38A>G	p.Asn13Ser	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.38A>G	p.Asn13Ser	missense_variant	Exon 2 of 12	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.*61A>G		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000465737.1
ENSG00000267699	ENST00000590722.2	n.*61A>G		3_prime_UTR_variant	Exon 3 of 9	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251334 AF XY: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33470

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111746

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:2

Feb 29, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Juvenile polyposis syndrome Uncertain:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 13 of the SMAD4 protein (p.Asn13Ser). This variant is present in population databases (rs281875323, gnomAD 0.0009%). This missense change has been observed in individual(s) with pulmonary arterial hypertension (PMID: 21898662). ClinVar contains an entry for this variant (Variation ID: 68788). 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. Experimental studies have shown that this missense change does not substantially affect SMAD4 function (PMID: 21898662, 25502805, 31515488). 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. -

Jun 23, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Uncertain:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Sep 07, 2018

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: SMAD4 c.38A>G (p.Asn13Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249274 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.38A>G in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. This variant has been described in a patient with idiopathic pulmonary arterial hypertension (Nasim 2011). At least two publications reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect for the variant on protein stability, subcellular localization, signaling activity and interactions with Smad3, Lmo4, Rassf5, and Smad9 (Nasim 2011, Wei 2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1 Other:1

Jul 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: did not impact SMAD-mediated signaling or interaction with Lmo4, Rassf5 and Smad9 (Nasim et al., 2011; Wei et al., 2014); Reported in an individual with idiopathic pulmonary arterial hypertension and in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Nasim et al., 2011; Bodian et al., 2014); This variant is associated with the following publications: (PMID: 25502805, 26387786, 21898662, 30084161, 24728327, 31515488) -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 17, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 13 of the SMAD4 protein. Computational prediction suggests that this variant may not impact protein structure and function. Protein interaction studies have shown this variant to behave like wild-type for binding to SMAD3 and SMAD9 (PMID: 25502805, 31515488). This variant has not been reported in individuals affected with SMAD4-related disorders in the literature. This variant has been identified in 3/251334 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. -

Pulmonary hypertension, primary, 1 Uncertain:1

-

Rare Disease Genomics Group, St George's University of London

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Aug 02, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T;T;T;T;T;T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	-0.23	.;N;.;.;.;N;.;.
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.38	.;N;.;.;.;N;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.74	.;T;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.99	.;D;.;.;.;D;.;.
Vest4		0.54, 0.54, 0.53
MutPred		0.17		Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);Gain of disorder (P = 0.0436);
MVP		0.72
MPC		1.2
ClinPred		0.47	T
GERP RS		5.9
PromoterAI		0.012	Neutral
Varity_R		0.12
gMVP		0.55
Mutation Taster		=47/53	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: rs281875323; hg19: chr18-48573454;