rs80232004
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005585.5(SMAD6):c.362G>A(p.Cys121Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,231,328 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005585.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMAD6 | NM_005585.5 | c.362G>A | p.Cys121Tyr | missense_variant | Exon 1 of 4 | ENST00000288840.10 | NP_005576.3 | |
SMAD6 | NR_027654.2 | n.1385G>A | non_coding_transcript_exon_variant | Exon 1 of 5 | ||||
SMAD6 | XR_931827.3 | n.1385G>A | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMAD6 | ENST00000288840.10 | c.362G>A | p.Cys121Tyr | missense_variant | Exon 1 of 4 | 1 | NM_005585.5 | ENSP00000288840.5 | ||
SMAD6 | ENST00000557916.5 | n.362G>A | non_coding_transcript_exon_variant | Exon 1 of 5 | 1 | ENSP00000452955.1 | ||||
SMAD6 | ENST00000612349.1 | n.544G>A | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes AF: 0.00124 AC: 188AN: 151010Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000798 AC: 7AN: 8770Hom.: 0 AF XY: 0.000853 AC XY: 4AN XY: 4690
GnomAD4 exome AF: 0.000383 AC: 414AN: 1080210Hom.: 1 Cov.: 31 AF XY: 0.000345 AC XY: 177AN XY: 513618
GnomAD4 genome AF: 0.00123 AC: 186AN: 151118Hom.: 1 Cov.: 33 AF XY: 0.00143 AC XY: 106AN XY: 73880
ClinVar
Submissions by phenotype
Aortic valve disease 2 Uncertain:1Benign:1
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not specified Benign:2
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Variant summary: SMAD6 c.362G>A (p.Cys121Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 1231328 control chromosomes, predominantly at a frequency of 0.013 within the Latino subpopulation in the gnomAD database v4. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 415.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.362G>A in individuals affected with Aortic Valve Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 436796). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at