rs2276163

chr18-51049019-T-C

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.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

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=-0.83).
• BP6: Variant 18-51049019-T-C is Benign according to our data. Variant chr18-51049019-T-C is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
SMAD4	NM_005359.6	c.424+159T>C		intron_variant		ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.424+159T>C		intron_variant		5	NM_005359.6	P1

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

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.410

Alfa AF: 0.381 Hom.: 1811

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.3
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: rs2276163; hg19: chr18-48575389; COSMIC: COSV61685503; COSMIC: COSV61685503;