chr18-51067097-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.1218G>A(p.Ala406Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,611,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_005359.6 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD4 | NM_005359.6 | c.1218G>A | p.Ala406Ala | synonymous_variant | Exon 10 of 12 | ENST00000342988.8 | NP_005350.1 | |
SMAD4 | NM_001407041.1 | c.1218G>A | p.Ala406Ala | synonymous_variant | Exon 10 of 12 | NP_001393970.1 | ||
SMAD4 | NM_001407042.1 | c.1218G>A | p.Ala406Ala | synonymous_variant | Exon 10 of 12 | NP_001393971.1 | ||
SMAD4 | NR_176265.1 | n.1756G>A | non_coding_transcript_exon_variant | Exon 10 of 13 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251474Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1459510Hom.: 0 Cov.: 29 AF XY: 0.0000289 AC XY: 21AN XY: 726264
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74454
ClinVar
Submissions by phenotype
not provided Benign:4
- -
Variant summary: The c.1218G>A (p.Ala406=) in SMAD4 gene is a synonymous change that involves a non-conserved nucleotide. 3/5 programs in Alamut predict that this variant may have some mild effect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies 0.000036 (4/121400 and 10/ 277190 chrs tested, respectively). However, the possibility of the variant to be derived from pseudogene cannot be completely ruled out. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. -
SMAD4: BP4, BP7 -
The SMAD4 c.1218G>A;p.Ala406Ala variant has not been published in the medical literature or in gene-specific databases. The variant is listed in the ClinVar database (Variation ID: 231979) and the dbSNP variant database (rs145097078) with an allele frequency of 0.0077 percent (1/13005 alleles) in the Exome Variant Server and 0.003608 percent (10/277190 alleles). The nucleotide at this position is not well conserved across species and computational algorithms predict this variant will not significant alter splicing. Considering available information, this variant is classified as likely benign. -
Hereditary cancer-predisposing syndrome Benign:2
- -
- -
not specified Benign:1
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. -
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/hereditary hemorrhagic telangiectasia syndrome Benign:1
- -
Juvenile polyposis syndrome Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at