rs1312566534
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_005359.6(SMAD4):c.787+21dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,459,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SMAD4
NM_005359.6 intron
NM_005359.6 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.187
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 18-51058259-T-TA is Benign according to our data. Variant chr18-51058259-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 492496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000123 (18/1459238) while in subpopulation EAS AF= 0.000453 (18/39700). AF 95% confidence interval is 0.000293. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAdExome4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.787+21dup | intron_variant | ENST00000342988.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMAD4 | ENST00000342988.8 | c.787+21dup | intron_variant | 5 | NM_005359.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 151824Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251366Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135846
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459238Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 725896
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1AN: 151824Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74172
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?
Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 08, 2017 | - - |
Juvenile polyposis syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at