rs377767376

Variant names:

• chr18-51078394-T-TA
• rs377767376
• NM_005359.6:c.1587dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005359.6(SMAD4):​c.1587dupA​(p.His530ThrfsTer47) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H530H) 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: 0.100
• Publications: 5 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: Likely_pathogenic. The variant received 8 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51078394-T-TA is Pathogenic according to our data. Variant chr18-51078394-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 24867.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.1587dupA	p.His530ThrfsTer47	frameshift_variant	Exon 12 of 12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1587dupA	p.His530ThrfsTer47	frameshift_variant	Exon 12 of 12		NP_001393970.1
SMAD4	NM_001407042.1	c.1587dupA	p.His530ThrfsTer47	frameshift_variant	Exon 12 of 12		NP_001393971.1
SMAD4	NR_176265.1	n.2238dupA		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1587dupA	p.His530ThrfsTer47	frameshift_variant	Exon 12 of 12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile polyposis syndrome Pathogenic:1

Sep 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the SMAD4 gene (p.His530Thrfs*47). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acids of the SMAD4 protein and extend the protein by an additional 24 amino acids. For these reasons, this variant has been classified as Pathogenic. This variant has been reported in an individual affected with juvenile polyposis syndrome (PMID: 18178612, 26572829). It has also been observed to be de novo in an individual affected with juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome (Invitae). This variant is also known as c.1586_1587dupA (p.L529LfsX9) in the literature. ClinVar contains an entry for this variant (Variation ID: 24867). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.10
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs377767376; hg19: chr18-48604764; COSMIC: COSV61687828; COSMIC: COSV61687828;