chr18-51047173-T-G

Position:

• chr18-51047173-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_005359.6(SMAD4):​c.127T>G​(p.Leu43Val) 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 pathogenic 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:2
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain MH1 (size 124) in uniprot entity SMAD4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.127T>G	p.Leu43Val	missense_variant	2/12	ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.127T>G	p.Leu43Val	missense_variant	2/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Sep 11, 2020

The p.L43V variant (also known as c.127T>G), located in coding exon 1 of the SMAD4 gene, results from a T to G substitution at nucleotide position 127. The leucine at codon 43 is replaced by valine, an amino acid with highly similar properties. In one functional study, this variant had reduced ability to transactivate a TGF-β responsive reporter gene and lost binding activity to a SMAD-binding element in an electrophoretic mobility shift assay (EMSA) (Kuang C et al. Oncogene, 2004 Feb;23:1021-9). 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

Invitae

Mar 24, 2023

Experimental studies have shown that this missense change affects SMAD4 function (PMID: 14647410). 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. 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 216602). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 43 of the SMAD4 protein (p.Leu43Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D;D;D;D;D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;M;.;.
MutationTaster	Benign	0.90	D;D;D;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;T;T;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.85, 0.86
MutPred		0.71		Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);Gain of methylation at K45 (P = 0.0789);
MVP		0.95
MPC		2.8
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.93
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: rs863224731; hg19: chr18-48573543;