rs80338965

Variant names:

• chr18-51067120-TAGAC-T
• rs80338965
• NM_005359.6:c.1245_1248delCAGA

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_005359.6(SMAD4):​c.1245_1248delCAGA​(p.Asp415GlufsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000966985: "In vitro functional studies provide some evidence that the p.Asp415GlufsX20 variant may impact protein function (Car r 2012)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D415D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMAD4 NM_005359.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 9.89
• Publications: 26 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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000966985: "In vitro functional studies provide some evidence that the p.Asp415GlufsX20 variant may impact protein function (Car r 2012)."; SCV001338144: Experimental evidence evaluating an impact on protein function demonstrated the variant leads to decreased bone morphogenetic protein signaling (Carr_2012).; SCV000211665: Published functional studies demonstrate a damaging effect: decreased BMP-mediated transcriptional activity (Carr et al., 2012); PMID: 24506336; SCV000889841: In a functional study, the variant reduced downstream bone morphogenic protein signaling in vitro (PMID: 22316667 (2012)).; SCV000898987: An in vitro functional study showed significantly decreased luciferase activity with this deletion, which is suggested to have a negative impact on downstream BMP signaling (Carr 2012 PMID:22316667).; SCV001552894: In HEK-293T cells, expression of the variant decreased bone morphogenetic protein signaling (Carr 2012).; SCV000186232: A functional study showed this mutation leads to a 33% reduction in luciferase activity compared to wild-type, indicating that the mutation negatively impacted downstream bone morphogenetic protein (BMP) pathway signaling (Carr, 2012).; SCV003924246: An in vitro functional study showed significantly decreased luciferase activity with this deletion, which is suggested to have a negative impact on downstream BMP signaling (Carr 2012 PMID:22316667).; SCV005361048: "In vitro functional studies suggest this variant impacts protein function (described as Del AGAC 1244-47 D415EfsX20 in Carr et al. 2012. PubMed ID: 22316667)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-51067120-TAGAC-T is Pathogenic according to our data. Variant chr18-51067120-TAGAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 142253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1245_1248delCAGA	p.Asp415GlufsTer20	frameshift	Exon 10 of 12	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.1245_1248delCAGA	p.Asp415GlufsTer20	frameshift	Exon 10 of 12	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.1245_1248delCAGA	p.Asp415GlufsTer20	frameshift	Exon 10 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.1245_1248delCAGA	p.Asp415GlufsTer20	frameshift	Exon 10 of 12	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3246_3249delCAGA		non_coding_transcript_exon	Exon 6 of 8
	SMAD4	ENST00000714264.1		c.1326_1329delCAGA	p.Asp442GlufsTer20	frameshift	Exon 10 of 12	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458726 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 725948

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109148

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Generalized juvenile polyposis/juvenile polyposis coli (4)
3	-	-	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (3)
2	-	-	Juvenile polyposis syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Carcinoma of pancreas;C0345893:Juvenile polyposis syndrome;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1)
1	-	-	Carcinoma of pancreas;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;C1868081:Generalized juvenile polyposis/juvenile polyposis coli (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	SMAD4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
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

Other links and lift over

dbSNP: rs80338965; hg19: chr18-48593490; COSMIC: COSV61684290;