rs672601247

Variant names:

• chr18-51047235-AAATGGAGC-NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN
• NM_005359.6:c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_005359.6(SMAD4):​c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN​(p.Thr63fs) variant causes a frameshift, missense change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T63T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 N/A (N/A hom., cov:)
  • Exomes 𝑓: N/A (N/A hom.)
• Consequence: SMAD4 NM_005359.6 frameshift, missense
• Clinical Significance: Not reported in ClinVar
• Conservation: No conservation score assigned
• 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Myhre syndrome

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

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

ENSG00000267699 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005359.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	NM_005359.6	MANE Select	c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN	p.Thr63fs	frameshift missense	Exon 2 of 12	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN	p.Thr63fs	frameshift missense	Exon 2 of 12	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN	p.Thr63fs	frameshift missense	Exon 2 of 12	NP_001393971.1	Q13485

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD4	ENST00000342988.8	TSL:5 MANE Select	c.189_197delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN	p.Thr63fs	frameshift missense	Exon 2 of 12	ENSP00000341551.3	Q13485
	ENSG00000267699	ENST00000590722.2	TSL:2	n.*212_*220delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN		non_coding_transcript_exon	Exon 3 of 9	ENSP00000465737.1	E7EUB6
	ENSG00000267699	ENST00000590722.2	TSL:2	n.*212_*220delAAATGGAGCinsNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN		3_prime_UTR	Exon 3 of 9	ENSP00000465737.1	E7EUB6

Frequencies

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

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Splicing

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

Other links and lift over

hg19: chr18-48573605;