18-51045117-T-G

Position:

• chr18-51045117-T-G

Variant summary

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

The NM_005359.6(SMAD4):​c.-127-1803T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,888 control chromosomes in the GnomAD database, including 9,708 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 0.35 (9707 hom., cov: 32)
  • Exomes 𝑓: 0.29 (1 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.355

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.-127-1803T>G		intron_variant		ENST00000342988.8	NP_005350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.-127-1803T>G		intron_variant		5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53611 AN: 151756 Hom.: 9698 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.373

GnomAD4 exome AF: 0.286 AC: 4 AN: 14 Hom.: 1 AF XY: 0.125 AC XY: 1 AN XY: 8

Gnomad4 NFE exome AF: 0.286

GnomAD4 genome AF: 0.353 AC: 53667 AN: 151874 Hom.: 9707 Cov.: 32 AF XY: 0.353 AC XY: 26192 AN XY: 74240

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.403

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.377

Alfa AF: 0.348 Hom.: 1166

Bravo AF: 0.355

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3764466; hg19: chr18-48571487; COSMIC: COSV61688234; COSMIC: COSV61688234;