rs1060500751

Positions:

• chr15-66703576-CGT-AGG

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.563

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]

SMAD6 (HGNC:):

ACMG classification

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
SMAD6	NM_005585.5	c.318_320delCGTinsAGG	p.AspVal106GluGly	missense_variant		ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1341_1343delCGTinsAGG		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1341_1343delCGTinsAGG		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.318_320delCGTinsAGG	p.AspVal106GluGly	missense_variant		1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.318_320delCGTinsAGG		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.500_502delCGTinsAGG		non_coding_transcript_exon_variant	1/1	6

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

Submissions by phenotype

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 30, 2016

This 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060500751; hg19: chr15-66995914;