rs377767373

Positions:

• chr18-51078354-CAG-C
• chr18-51078354-CAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005359.6(SMAD4):​c.1549_1550del​(p.Ser517HisfsTer9) variant causes a frameshift change involving the alteration of a 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. Q516Q) 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, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.17

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 18 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 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51078354-CAG-C is Pathogenic according to our data. Variant chr18-51078354-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1549_1550del	p.Ser517HisfsTer9	frameshift_variant	12/12	ENST00000342988.8
SMAD4	NM_001407041.1	c.1549_1550del	p.Ser517HisfsTer9	frameshift_variant	12/12
SMAD4	NM_001407042.1	c.1549_1550del	p.Ser517HisfsTer9	frameshift_variant	12/12
SMAD4	NR_176265.1	n.2200_2201del		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1549_1550del	p.Ser517HisfsTer9	frameshift_variant	12/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2017

This deletion of two nucleotides in SMAD4 is denoted c.1549_1550delAG at the cDNA level and p.Ser517HisfsX9 (S517HfsX9) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAG[delAG]CATC. The deletion causes a frameshift which changes a Serine to a Histidine at codon 517, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. SMAD4 Ser517HisfsX9, also known as c.(1546-1548)CAGfs using alternate nomenclature, has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a pancreatic tumor (Witkiewicz 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2019

The c.1549_1550delAG pathogenic mutation, located in coding exon 11 of the SMAD4 gene, results from a deletion of two nucleotides at nucleotide positions 1549 to 1550, causing a translational frameshift with a predicted alternate stop codon (p.S517Hfs*9). This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 20, 2023

- -

Juvenile polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SMAD4 protein. Other variant(s) that disrupt this region (p.Ala532Profs*5) have been determined to be pathogenic (PMID: 15031030). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 545806). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Ser517Hisfs*9). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the SMAD4 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377767373; hg19: chr18-48604724;