rs17663887

chr18-51063348-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005359.6(SMAD4):c.956-2075T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 152,204 control chromosomes in the GnomAD database, including 265 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 0.054 (265 hom., cov: 31)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.956-2075T>C		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.956-2075T>C		intron_variant		5	NM_005359.6	P1

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8259 AN: 152086 Hom.: 265 Cov.: 31

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0475

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.0485

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.0346

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

GnomAD4 genome AF: 0.0542 AC: 8255 AN: 152204 Hom.: 265 Cov.: 31 AF XY: 0.0533 AC XY: 3963 AN XY: 74404

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0475

Gnomad4 EAS AF: 0.0472

Gnomad4 SAS AF: 0.0486

Gnomad4 FIN AF: 0.0851

Gnomad4 NFE AF: 0.0813

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.0628 Hom.: 65

Bravo AF: 0.0482

Asia WGS AF: 0.0330 AC: 114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.3
Dann	Benign	0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs17663887; hg19: chr18-48589718;