18-51048790-G-A

Position:

chr18-51048790-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005359.6(SMAD4):c.354G>A(p.Ala118Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,613,918 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 17 hom. )

Consequence

SMAD4
NM_005359.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: -0.204

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:

ENSG00000267699 (HGNC:):

ENSG00000267699 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 18-51048790-G-A is Benign according to our data. Variant chr18-51048790-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 24799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-51048790-G-A is described in Lovd as [Benign]. Variant chr18-51048790-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.204 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00256 (390/152224) while in subpopulation NFE AF= 0.00428 (291/68024). AF 95% confidence interval is 0.00387. There are 0 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 390 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD4	NM_005359.6 linkuse as main transcript	c.354G>A	p.Ala118Ala	synonymous_variant	3/12	ENST00000342988.8	NP_005350.1	Q13485A0A024R274

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMAD4	ENST00000342988.8 linkuse as main transcript	c.354G>A	p.Ala118Ala	synonymous_variant	3/12	5	NM_005359.6	ENSP00000341551.3	Q13485
ENSG00000267699	ENST00000590722.2 linkuse as main transcript	n.*377G>A		non_coding_transcript_exon_variant	4/9	2		ENSP00000465737.1	E7EUB6
ENSG00000267699	ENST00000590722.2 linkuse as main transcript	n.*377G>A		3_prime_UTR_variant	4/9	2		ENSP00000465737.1	E7EUB6

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

390

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00303

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00428

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00276

AC:

693

AN:

251432

Hom.:

AF XY:

0.00262

AC XY:

356

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.00459

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00384

AC:

5613

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

2716

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00470

Gnomad4 NFE exome

AF:

0.00460

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00256

AC:

390

AN:

152224

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

188

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00303

Gnomad4 NFE

AF:

0.00428

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00340

Hom.:

Bravo

AF:

0.00218

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 08, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SMAD4: BP4, BP7, BS1, BS2 -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 25, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 08, 2017	- -

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. -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The SMAD4 p.Ala118= variant was identified in 1 of 140 proband chromosomes (frequency: 0.007) from individuals or families with Juvenile polyposis syndrome (Pyatt 2006). The variant was also identified in dbSNP (ID: rs145988618) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, and ARUP; as likely benign by 7 submitters), Cosmic (2X in large intestine tissue), LOVD 3.0 (4x as benign or likely benign), and in ARUP Laboratories (as benign). The variant was identified in control databases in 768 of 277174 chromosomes (3 homozygous) at a frequency of 0.003 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 23 of 24032 chromosomes (freq: 0.0009), Other in 13 of 6462 chromosomes (freq: 0.002), Latino in 21 of 34418 chromosomes (freq: 0.0006), European in 572 of 126678 chromosomes (freq: 0.005), Ashkenazi Jewish in 3 of 10150 chromosomes (freq: 0.0003), Finnish in 132 of 25786 chromosomes (freq: 0.005), and South Asian in 4 of 30782 chromosomes (freq: 0.0001); it was not observed in the East Asian, population. The p.Ala118= 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. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 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. -

Generalized juvenile polyposis/juvenile polyposis coli

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Juvenile polyposis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.1

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