rs16952790

Variant names:

• chr18-51068528-A-G
• rs16952790
• NM_005359.6:c.1308+1341A>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+1341A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 152,288 control chromosomes in the GnomAD database, including 581 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 0.047 (581 hom., cov: 32)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.729
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 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+1341A>G		intron	N/A	NP_005350.1	Q13485
	SMAD4	NM_001407041.1		c.1308+1341A>G		intron	N/A	NP_001393970.1	A0A024R274
	SMAD4	NM_001407042.1		c.1308+1341A>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+1341A>G		intron	N/A	ENSP00000341551.3	Q13485
	SMAD4	ENST00000591126.5	TSL:1	n.3309+1341A>G		intron	N/A
	SMAD4	ENST00000714264.1		c.1389+1341A>G		intron	N/A	ENSP00000519545.1	A0AAQ5BHY6

Frequencies

GnomAD3 genomes AF: 0.0465 AC: 7083 AN: 152170 Hom.: 577 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.0445

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

GnomAD4 genome AF: 0.0467 AC: 7118 AN: 152288 Hom.: 581 Cov.: 32 AF XY: 0.0454 AC XY: 3382 AN XY: 74476

African (AFR) AF: 0.158 AC: 6571 AN: 41524

American (AMR) AF: 0.0209 AC: 320 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68034

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

Alfa AF: 0.0267 Hom.: 84

Bravo AF: 0.0537

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.52
PhyloP100		0.73
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

Other links and lift over

dbSNP: rs16952790; hg19: chr18-48594898;