18-51078319-GTT-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005359.6(SMAD4):c.1515del(p.Phe505LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S504S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0910

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51078319-GT-G is Pathogenic according to our data. Variant chr18-51078319-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219788.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1515del	p.Phe505LeufsTer2	frameshift_variant	12/12	ENST00000342988.8
SMAD4	NM_001407041.1	c.1515del	p.Phe505LeufsTer2	frameshift_variant	12/12
SMAD4	NM_001407042.1	c.1515del	p.Phe505LeufsTer2	frameshift_variant	12/12
SMAD4	NR_176265.1	n.2166del		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1515del	p.Phe505LeufsTer2	frameshift_variant	12/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized juvenile polyposis/juvenile polyposis coli Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2015

This sequence change deletes 1 nucleotide from exon 12 of the SMAD4 mRNA (c.1512delT), causing a frameshift at codon 505. This creates a premature translational stop signal in the last exon of the SMAD4 mRNA (p.Phe505Leufs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated SMAD4 protein. While this particular sequence change has not been reported in the literature, truncating sequence changes in SMAD4 are known to be pathogenic (PMID: 22810475, 16152648). For these reasons, this variant has been classified as Likely Pathogenic. -

Juvenile polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 04, 2018

This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Phe505Leufs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acids of the SMAD4 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. A different truncation (p.His530Thrfs*47) that lies downstream of this variant has been determined to be pathogenic (PMID: 18178612, Invitae). This suggests that deletion of this region of the SMAD4 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs864622252; hg19: chr18-48604689;