chr18-51078442-T-A

Position:

• chr18-51078442-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_005359.6(SMAD4):​c.1634T>A​(p.Ile545Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.15

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a domain MH2 (size 229) in uniprot entity SMAD4_HUMAN there are 40 pathogenic changes around while only 2 benign (95%) in NM_005359.6
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD4. . Gene score misZ 4.1308 (greater than the threshold 3.09). Trascript score misZ 4.9346 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, generalized juvenile polyposis/juvenile polyposis coli, hereditary hemorrhagic telangiectasia, Myhre syndrome, pulmonary arterial hypertension, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1634T>A	p.Ile545Asn	missense_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1634T>A	p.Ile545Asn	missense_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1	c.1634T>A	p.Ile545Asn	missense_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1	n.2285T>A		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1634T>A	p.Ile545Asn	missense_variant	12/12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2014

This variant is denoted SMAD4 c.1634T>A at the cDNA level, p.Ile545Asn (I545N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Ile545Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Asparagine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SMAD4 Ile545Asn occurs at a position that is well conserved across species and is located in the C-terminal MH2 functional domain. In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether SMAD4 Ile545Asn is pathogenic or benign. We consider it to be a variant of uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2019

The p.I545N variant (also known as c.1634T>A), located in coding exon 11 of the SMAD4 gene, results from a T to A substitution at nucleotide position 1634. The isoleucine at codon 545 is replaced by asparagine, an amino acid with dissimilar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 545 of the SMAD4 protein (p.Ile545Asn). 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: 182872). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D;D;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.93	P;P;.
Vest4		0.55
MutPred		0.30		Gain of disorder (P = 0.0166);Gain of disorder (P = 0.0166);.;
MVP		0.93
MPC		2.7
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.80
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs730881955; hg19: chr18-48604812;