rs2276163

Variant names:

• chr18-51049019-T-C
• rs2276163
• NM_005359.6:c.424+159T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005359.6(SMAD4):​c.424+159T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 152,112 control chromosomes in the GnomAD database, including 11,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.39 (11435 hom., cov: 33)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.239
• Publications: 8 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), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-51049019-T-C is Benign according to our data. Variant chr18-51049019-T-C is described in ClinVar as Benign. ClinVar VariationId is 1234168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.424+159T>C		intron_variant	Intron 3 of 11	ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.424+159T>C		intron_variant	Intron 3 of 11	5	NM_005359.6	ENSP00000341551.3
ENSG00000267699	ENST00000590722.2	n.*447+159T>C		intron_variant	Intron 4 of 8	2		ENSP00000465737.1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58738 AN: 151994 Hom.: 11419 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.406

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

GnomAD4 genome AF: 0.387 AC: 58815 AN: 152112 Hom.: 11435 Cov.: 33 AF XY: 0.384 AC XY: 28589 AN XY: 74364

African (AFR) AF: 0.389 AC: 16133 AN: 41496

American (AMR) AF: 0.403 AC: 6158 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1402 AN: 3472

East Asian (EAS) AF: 0.452 AC: 2345 AN: 5188

South Asian (SAS) AF: 0.253 AC: 1223 AN: 4826

European-Finnish (FIN) AF: 0.395 AC: 4171 AN: 10562

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25843 AN: 67982

Other (OTH) AF: 0.410 AC: 866 AN: 2110

Alfa AF: 0.382 Hom.: 1883

Bravo AF: 0.395

Asia WGS AF: 0.379 AC: 1312 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.3
DANN	Benign	0.65
PhyloP100		-0.24
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: rs2276163; hg19: chr18-48575389; COSMIC: COSV61685503; COSMIC: COSV61685503;