18-51078459-T-G

Position:

• chr18-51078459-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_005359.6(SMAD4):​c.1651T>G​(p.Leu551Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.62

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 Uncertain_significance. Variant got 3 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
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1399889).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1651T>G	p.Leu551Val	missense_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1651T>G	p.Leu551Val	missense_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1	c.1651T>G	p.Leu551Val	missense_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1	n.2302T>G		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1651T>G	p.Leu551Val	missense_variant	12/12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2024

The p.L551V variant (also known as c.1651T>G), located in coding exon 11 of the SMAD4 gene, results from a T to G substitution at nucleotide position 1651. The leucine at codon 551 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2015

This variant is denoted SMAD4 c.1651T>G at the cDNA level, p.Leu551Val (L551V) at the protein level, and results in the change of a Leucine to a Valine (TTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Leu551Val 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 Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Leu551Val occurs at a position that is conserved across species and is located in the MH2 domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether SMAD4 Leu551Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Carcinoma of pancreas;C0345893:Juvenile polyposis syndrome;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 03, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 08, 2019

This missense variant replaces leucine with valine at codon 551 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

ClinVar contains an entry for this variant (Variation ID: 419554). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 551 of the SMAD4 protein (p.Leu551Val). 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. 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	Benign	0.094
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	0.29	N;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.74	N;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.62	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.47	P;P;.
Vest4		0.31
MutPred		0.15		Gain of disorder (P = 0.2488);Gain of disorder (P = 0.2488);.;
MVP		0.84
MPC		1.6
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.21
gMVP		0.53

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: rs1064793950; hg19: chr18-48604829;