rs9304407

Variant names:

• chr18-51069023-C-G
• rs9304407
• NM_005359.6:c.1308+1836C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005359.6(SMAD4):​c.1308+1836C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,042 control chromosomes in the GnomAD database, including 25,747 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (25747 hom., cov: 32)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570
• Publications: 7 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), Genomics England PanelApp, PanelApp Australia, G2P, ClinGen
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

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.1308+1836C>G		intron	N/A	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.1308+1836C>G		intron	N/A	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.1308+1836C>G		intron	N/A	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.1308+1836C>G		intron	N/A	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3309+1836C>G		intron	N/A
	SMAD4	ENST00000714264.1		c.1389+1836C>G		intron	N/A	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82119 AN: 151924 Hom.: 25683 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.509

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

GnomAD4 genome AF: 0.541 AC: 82248 AN: 152042 Hom.: 25747 Cov.: 32 AF XY: 0.537 AC XY: 39867 AN XY: 74304

African (AFR) AF: 0.881 AC: 36589 AN: 41510

American (AMR) AF: 0.469 AC: 7165 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1605 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2804 AN: 5174

South Asian (SAS) AF: 0.335 AC: 1612 AN: 4812

European-Finnish (FIN) AF: 0.412 AC: 4342 AN: 10532

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26363 AN: 67956

Other (OTH) AF: 0.512 AC: 1078 AN: 2104

Alfa AF: 0.470 Hom.: 2440

Bravo AF: 0.568

Asia WGS AF: 0.471 AC: 1636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.77
DANN	Benign	0.60
PhyloP100		0.057
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9304407;

hg19: chr18-48595393;