chr18-51077033-T-C

Position:

• chr18-51077033-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005359.6(SMAD4):​c.1447+257T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 280,490 control chromosomes in the GnomAD database, including 22,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11734 hom., cov: 31)
  • Exomes 𝑓: 0.41 (10347 hom.)
• Consequence: SMAD4 NM_005359.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.767

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]

SMAD4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-51077033-T-C is Benign according to our data. Variant chr18-51077033-T-C is described in ClinVar as [Benign]. Clinvar id is 680785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.1447+257T>C		intron_variant		ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1	c.1447+257T>C		intron_variant			NP_001393970.1
SMAD4	NM_001407042.1	c.1447+257T>C		intron_variant			NP_001393971.1
SMAD4	NR_176265.1	n.1985+257T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.1447+257T>C		intron_variant		5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59442 AN: 151832 Hom.: 11713 Cov.: 31

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.409 AC: 52513 AN: 128540 Hom.: 10347 Cov.: 3 AF XY: 0.407 AC XY: 26444 AN XY: 64992

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.392 AC: 59527 AN: 151950 Hom.: 11734 Cov.: 31 AF XY: 0.389 AC XY: 28907 AN XY: 74256

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.417

Alfa AF: 0.378 Hom.: 1760

Bravo AF: 0.401

Asia WGS AF: 0.378 AC: 1313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.72

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: rs2298617; hg19: chr18-48603403;