rs1801250

Positions:

• chr18-51065553-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005359.6(SMAD4):​c.1086T>C​(p.Phe362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,186 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (12 hom.)
• Consequence: SMAD4 NM_005359.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 2.42

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 18-51065553-T-C is Benign according to our data. Variant chr18-51065553-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 132693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-51065553-T-C is described in Lovd as [Benign]. Variant chr18-51065553-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (340/152328) while in subpopulation AFR AF= 0.00397 (165/41562). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1086T>C	p.Phe362=	synonymous_variant	9/12	ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1086T>C	p.Phe362=	synonymous_variant	9/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00182 AC: 457 AN: 251414 Hom.: 3 AF XY: 0.00182 AC XY: 247 AN XY: 135886

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00135 AC: 1980 AN: 1461858 Hom.: 12 Cov.: 31 AF XY: 0.00134 AC XY: 976 AN XY: 727228

Gnomad4 AFR exome AF: 0.00624

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000931

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74488

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00263 Hom.: 1

Bravo AF: 0.00243

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2013	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. -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 24, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SMAD4: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2016	Variant summary: The c.1086T>C in SMAD4 gene is a synonymous change that involves a conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant was found in multiple affected individuals presented with personal and/or family history of cancer. It is present in the control population dataset of ExAC at frequency of 0.17%, including 2 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic SMAD4 variant, suggesting that it is a common polymorphism. However, some of these occurrences may potentially be due to a presence of a processed pseudogene, and, therefore, should be taken with cautions. Lastly, the variant has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken together, this variant has been classified as Benign. -

Generalized juvenile polyposis/juvenile polyposis coli Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SMAD4 p.Phe362= variant was identified in 2 of 1004 proband chromosomes (frequency: 0.002) from individuals or families with gastric or breast cancer and was present in 1 of 1420 control chromosomes (frequency: 0.001) from healthy individuals (Oliveira 2003, Tram 2011). The variant was also identified in dbSNP (ID: rs1801250) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color and ARUP; and as likely benign by Ambry Genetics and two other submitters), and in LOVD 3.0 (3x as benign or likely benign). The variant was identified in control databases in 502 of 277188 chromosomes (3 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 84 of 24028 chromosomes (freq: 0.003), Other in 28 of 6466 chromosomes (freq: 0.004), Latino in 103 of 34412 chromosomes (freq: 0.003), European in 133 of 126694 chromosomes (freq: 0.001), Ashkenazi Jewish in 149 of 10150 chromosomes (freq: 0.02), and South Asian in 5 of 30782 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian or Finnish populations. The p.Phe362= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 10, 2017	- -

Juvenile polyposis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Myhre syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 16, 2017

- -

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2014

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.7
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1801250; hg19: chr18-48591923; COSMIC: COSV61692346; COSMIC: COSV61692346;