rs1555687386

Variant names:

• chr18-51076734-A-ATCCC
• rs1555687386
• NM_005359.6:c.1407_1410dupCCCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005359.6(SMAD4):​c.1407_1410dupCCCT​(p.Gly471ProfsTer24) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G471G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51076734-A-ATCCC is Pathogenic according to our data. Variant chr18-51076734-A-ATCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 529945.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1407_1410dupCCCT	p.Gly471ProfsTer24	frameshift_variant	Exon 11 of 12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1407_1410dupCCCT	p.Gly471ProfsTer24	frameshift_variant	Exon 11 of 12		NP_001393970.1
SMAD4	NM_001407042.1	c.1407_1410dupCCCT	p.Gly471ProfsTer24	frameshift_variant	Exon 11 of 12		NP_001393971.1
SMAD4	NR_176265.1	n.1945_1948dupCCCT		non_coding_transcript_exon_variant	Exon 11 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1407_1410dupCCCT	p.Gly471ProfsTer24	frameshift_variant	Exon 11 of 12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile polyposis syndrome Pathogenic:1

Mar 14, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed to segregate with juvenile polyposis (JP) and colorectal cancer in a family (Invitae). In addition, a similar change (c.1409_1410insCCCT) giving rise to the same protein effect (p.Gly471Profs*24) has been observed in an individual with JP (PMID: 16287957). This sequence change results in a premature translational stop signal in the SMAD4 gene (p.Gly471Profs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acids of the SMAD4 protein. This variant is not present in population databases (ExAC no frequency). This variant is expected to delete a portion of the C-terminal region of the SMAD4 protein containing the MH2 domain (residues Trp323-Asp552) (PMID: 22243968). Although experimental studies have not been performed for this particular variant, deletion of the MH2 domain likely impairs complex formation of the SMAD4 protein for proper TGFβ signaling (PMID: 9389648, 12821112, 19135894). Downstream truncating variants affecting this domain have been observed in individuals affected with JP (PMID: 15031030). 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555687386; hg19: chr18-48603104;