rs12456284

Variant names:

• chr18-51083598-A-G
• rs12456284
• NM_005359.6:c.*5131A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-51083598-A-G
• chr18-51083598-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign; confers sensitivity criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.791
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Myhre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD4	NM_005359.6	c.*5131A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000342988.8	NP_005350.1
SMAD4	NR_176265.1	n.7441A>G		non_coding_transcript_exon_variant	Exon 13 of 13
SMAD4	NM_001407041.1	c.*5131A>G		3_prime_UTR_variant	Exon 12 of 12		NP_001393970.1
SMAD4	NM_001407042.1	c.*5131A>G		3_prime_UTR_variant	Exon 12 of 12		NP_001393971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD4	ENST00000342988.8	c.*5131A>G		3_prime_UTR_variant	Exon 12 of 12	5	NM_005359.6	ENSP00000341551.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30294 AN: 151950 Hom.: 3817 Cov.: 31

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.: 0 AF XY: 0.273 AC XY: 9510 AN XY: 34800

African (AFR) AF: 0.0557 AC: 202 AN: 3626

American (AMR) AF: 0.289 AC: 664 AN: 2300

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 1257 AN: 4810

East Asian (EAS) AF: 0.430 AC: 4637 AN: 10774

South Asian (SAS) AF: 0.205 AC: 133 AN: 648

European-Finnish (FIN) AF: 0.179 AC: 10 AN: 56

Middle Eastern (MID) AF: 0.266 AC: 124 AN: 466

European-Non Finnish (NFE) AF: 0.258 AC: 12025 AN: 46532

Other (OTH) AF: 0.246 AC: 1548 AN: 6300

GnomAD4 genome AF: 0.199 AC: 30307 AN: 152070 Hom.: 3820 Cov.: 31 AF XY: 0.203 AC XY: 15067 AN XY: 74318

African (AFR) AF: 0.0509 AC: 2112 AN: 41528

American (AMR) AF: 0.257 AC: 3919 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1871 AN: 5128

South Asian (SAS) AF: 0.188 AC: 905 AN: 4818

European-Finnish (FIN) AF: 0.290 AC: 3066 AN: 10568

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16517 AN: 67970

Other (OTH) AF: 0.246 AC: 519 AN: 2112

Alfa AF: 0.231 Hom.: 13864

Bravo AF: 0.197

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign; confers sensitivity

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myhre syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Generalized juvenile polyposis/juvenile polyposis coli Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Lung cancer Other:1

May 01, 2012

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

Significance: confers sensitivity

Review Status: criteria provided, single submitter

Collection Method: research

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	13
DANN	Benign	0.78
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12456284; hg19: chr18-48609968; COSMIC: COSV61687365;