rs12456284

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005359.6(SMAD4):c.*5131A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 227,582 control chromosomes in the GnomAD database, including 6,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,confers sensitivity (★★).

Frequency

Genomes: 𝑓 0.20 ( 3820 hom., cov: 31)

Exomes 𝑓: 0.27 ( 3089 hom. )

Consequence

SMAD4
NM_005359.6 3_prime_UTR

Scores

Clinical Significance

Benign; confers sensitivity criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.791

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 18-51083598-A-G is Benign according to our data. Variant chr18-51083598-A-G is described in ClinVar as [Benign, confers_sensitivity]. Clinvar id is 327175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
SMAD4	NM_005359.6 linkuse as main transcript	c.*5131A>G	3_prime_UTR_variant	12/12	ENST00000342988.8	NP_005350.1
SMAD4	NM_001407041.1 linkuse as main transcript	c.*5131A>G	3_prime_UTR_variant	12/12		NP_001393970.1
SMAD4	NM_001407042.1 linkuse as main transcript	c.*5131A>G	3_prime_UTR_variant	12/12		NP_001393971.1
SMAD4	NR_176265.1 linkuse as main transcript	n.7441A>G	non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8 linkuse as main transcript	c.*5131A>G		3_prime_UTR_variant	12/12	5	NM_005359.6	ENSP00000341551	P1

Frequencies

GnomAD3 genomes

AF:

0.199

AC:

30294

AN:

151950

Hom.:

3817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0510

Gnomad AMI

AF:

0.457

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.290

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.240

GnomAD4 exome

AF:

0.273

AC:

20600

AN:

75512

Hom.:

3089

Cov.:

AF XY:

0.273

AC XY:

9510

AN XY:

34800

show subpopulations

Gnomad4 AFR exome

AF:

0.0557

Gnomad4 AMR exome

AF:

0.289

Gnomad4 ASJ exome

AF:

0.261

Gnomad4 EAS exome

AF:

0.430

Gnomad4 SAS exome

AF:

0.205

Gnomad4 FIN exome

AF:

0.179

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.246

GnomAD4 genome

AF:

0.199

AC:

30307

AN:

152070

Hom.:

3820

Cov.:

AF XY:

0.203

AC XY:

15067

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0509

Gnomad4 AMR

AF:

0.257

Gnomad4 ASJ

AF:

0.261

Gnomad4 EAS

AF:

0.365

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.290

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.246

Alfa

AF:

0.242

Hom.:

8918

Bravo

AF:

0.197

Asia WGS

AF:

0.283

AC:

984

AN:

3478

ClinVar

Significance: Benign; confers sensitivity

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 03, 2018

- -

Myhre syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Lung cancer

Other:1

confers sensitivity, criteria provided, single submitter

research

Kong Lab, Department of Radiation Oncology, Case Western Reserve University School of Medicine

May 01, 2012

Improve the prediction accuracy for overal survival in non-small cell lung cancer patients -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over