rs1060500734

Variant names:

• chr18-51067076-CA-C
• rs1060500734
• NM_005359.6:c.1198delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005359.6(SMAD4):​c.1198delA​(p.Arg400GlyfsTer15) 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. R400R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.18

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51067076-CA-C is Pathogenic according to our data. Variant chr18-51067076-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1198delA	p.Arg400GlyfsTer15	frameshift_variant	Exon 10 of 12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1198delA	p.Arg400GlyfsTer15	frameshift_variant	Exon 10 of 12		NP_001393970.1
SMAD4	NM_001407042.1	c.1198delA	p.Arg400GlyfsTer15	frameshift_variant	Exon 10 of 12		NP_001393971.1
SMAD4	NR_176265.1	n.1736delA		non_coding_transcript_exon_variant	Exon 10 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1198delA	p.Arg400GlyfsTer15	frameshift_variant	Exon 10 of 12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 05, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1198delA pathogenic mutation, located in coding exon 9 of the SMAD4 gene, results from a deletion of one nucleotide at position 1198, causing a translational frameshift with a predicted alternate stop codon. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 02, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting c.1198del, located in exon 10 of the SMAD4 gene, consists in the deletion of one nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(Arg400Glyfs*15). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. This variant has been identified in an 42 year patient with multiple colorectal polyps (internal data).To our knowledge, functional studies have not been reported for this variant. In addition, it has been reported in ClinVar (2x as pathogenic) but has not been identified in LOVD database. Based on currently available information, the variant c.1198del is classified as a likely pathogenic variant according to according to ACMG guidelines. -

Juvenile polyposis syndrome Pathogenic:1

Aug 16, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in SMAD4 are known to be pathogenic (PMID: 22810475, 16152648). This sequence change deletes 1 nucleotide from exon 10 of the SMAD4 mRNA (c.1198delA), causing a frameshift at codon 400. This creates a premature translational stop signal (p.Arg400Glyfs*15) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500734; hg19: chr18-48593446;