rs8096092

chr18-51055231-C-Achr18-51055231-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005359.6(SMAD4):c.667+238C>A 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 151,950 control chromosomes in the GnomAD database, including 11,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.39 (11421 hom., cov: 32)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.710

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 18-51055231-C-A is Benign according to our data. Variant chr18-51055231-C-A is described in ClinVar as [Benign]. Clinvar id is 677079.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.667+238C>A		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.667+238C>A		intron_variant		5	NM_005359.6	P1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58704 AN: 151832 Hom.: 11405 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.397

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: 58781 AN: 151950 Hom.: 11421 Cov.: 32 AF XY: 0.385 AC XY: 28583 AN XY: 74276

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.403

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.410

Alfa AF: 0.381 Hom.: 1810

Bravo AF: 0.395

Asia WGS AF: 0.378 AC: 1310 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.14
Dann	Benign	0.25

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: rs8096092; hg19: chr18-48581601;