18-51048865-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_005359.6(SMAD4):c.424+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000185 in 1,608,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005359.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.424+5G>A | splice_region_variant, intron_variant | Intron 3 of 11 | ENST00000342988.8 | NP_005350.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.424+5G>A | splice_region_variant, intron_variant | Intron 3 of 11 | 5 | NM_005359.6 | ENSP00000341551.3 | |||
ENSG00000267699 | ENST00000590722.2 | n.*447+5G>A | splice_region_variant, intron_variant | Intron 4 of 8 | 2 | ENSP00000465737.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 151834Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000219 AC: 55AN: 250792Hom.: 0 AF XY: 0.000229 AC XY: 31AN XY: 135584
GnomAD4 exome AF: 0.000191 AC: 278AN: 1456686Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 154AN XY: 724816
GnomAD4 genome AF: 0.000125 AC: 19AN: 151952Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
The frequency of this variant in the general population, 0.00037 (47/128762 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 31159747 (2019), 30426508 (2018), and 25186627 (2015)), pancreatic cancer (PMID: 28726808 (2018)), gastric cancer (PMID: 32066632 (2021)), colon cancer (PMID: 25980754 (2015)), and hamartomatous polyposis syndrome (PMID: 2714957 (2016)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SMAD4 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
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In silico analysis supports that this variant does not alter splicing; however, published functional studies demonstrate evidence of aberrant splicing (Shiraishi Y et al. Systematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data. bioRxiv. October 7, 2021); Observed in individuals with Lynch syndrome-associated cancer, familial gastric cancer, pancreatic cancer, breast cancer, or polyps, but has not been published in individuals with connective tissue disorders to our knowledge (PMID: 25186627, 27146957, 28726808, 30426508, 32066632, 34326862, 35534704); This variant is associated with the following publications: (PMID: 32066632, 25980754, 28873162, 31159747, 27146957, Shiraishi2021, 25186627, 28726808, 30426508, 35534704, 34326862) -
SMAD4: BP4, BS2 -
The SMAD4 c.424+5G>A variant (rs200772603) is reported in the literature in an individual with suspected Lynch syndrome (Yurgelun 2015) and another individual referred for hereditary cancer testing (Tsaousis 2019). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (47/128762 alleles) in the Genome Aggregation Database. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.424+5G>A variant is uncertain at this time. References: Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. -
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not specified Uncertain:1Benign:2
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Variant summary: SMAD4 c.424+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant abolishes a 5 splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 250792 control chromosomes. The observed variant frequency is approximately 110 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD4 causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. c.424+5G>A has been reported in the literature in individuals affected with cancer including colorectal cancer, hereditary breast and ovarian cancer, pancreatic ductal adenocarcinoma and familial intestinal gastric cancer (e.g. Tung_2015, Yurgelun_2015, Mandelker_2017, Chaffee_2018, Schubert_2019, Tsaousis_2019, Carvalho_2021). These reports do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25186627, 27146957, 28873162, 28726808, 30426508, 31159747, 32066632). ClinVar contains an entry for this variant (Variation ID: 127950). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Uncertain:1Benign:1
This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Generalized juvenile polyposis/juvenile polyposis coli Benign:2
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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. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
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Myhre syndrome Benign:1
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. -
SMAD4-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
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 syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at