rs12958604

chr18-51033955-A-G

Variant summary

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

The NM_005359.6(SMAD4):c.-128+3332A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 152,090 control chromosomes in the GnomAD database, including 8,986 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 0.33 (8986 hom., cov: 31)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0310

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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.-128+3332A>G		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.-128+3332A>G		intron_variant		5	NM_005359.6	P1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50274 AN: 151972 Hom.: 8982 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.331 AC: 50317 AN: 152090 Hom.: 8986 Cov.: 31 AF XY: 0.330 AC XY: 24544 AN XY: 74328

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.402

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.361

Alfa AF: 0.362 Hom.: 4873

Bravo AF: 0.329

Asia WGS AF: 0.359 AC: 1246 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.46
Dann	Benign	0.65

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: rs12958604; hg19: chr18-48560325;