rs1060500751

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005585.5(SMAD6):​c.318_320delCGTinsAGG​(p.AspVal106GluGly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SMAD6
NM_005585.5 missense

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.563
Variant links:
Genes affected
SMAD6 (HGNC:6772): (SMAD family member 6) The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMAD6NM_005585.5 linkuse as main transcriptc.318_320delCGTinsAGG p.AspVal106GluGly missense_variant ENST00000288840.10 NP_005576.3 O43541-1
SMAD6NR_027654.2 linkuse as main transcriptn.1341_1343delCGTinsAGG non_coding_transcript_exon_variant 1/5
SMAD6XR_931827.3 linkuse as main transcriptn.1341_1343delCGTinsAGG non_coding_transcript_exon_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMAD6ENST00000288840.10 linkuse as main transcriptc.318_320delCGTinsAGG p.AspVal106GluGly missense_variant 1 NM_005585.5 ENSP00000288840.5 O43541-1
SMAD6ENST00000557916.5 linkuse as main transcriptn.318_320delCGTinsAGG non_coding_transcript_exon_variant 1/51 ENSP00000452955.1 O43541-4
SMAD6ENST00000612349.1 linkuse as main transcriptn.500_502delCGTinsAGG non_coding_transcript_exon_variant 1/16

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aortic valve disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 30, 2016This sequence change deletes 3 nucleotides and inserts 3 in exon 1 of the SMAD6 mRNA (c.318_320delinsAGG). This leads to the deletion of 2 amino acid residues in the SMAD6 protein and the insertion of glutamic acid and glycine (p.Asp106_Val107delinsGluGly) but otherwise preserves the integrity of the reading frame. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. Experimental studies evaluating the effect of this in-frame deletion have not been published. In summary, this is a novel in-frame change with an unknown effect on protein function. For these reasons it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs1060500751; hg19: chr15-66995914; API