15-66703257-GTATGT-G

Variant names:

• chr15-66703257-GTATGT-G
• NM_005585.5:c.1_5delATGTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005585.5(SMAD6):​c.1_5delATGTT​(p.Met1fs) variant causes a frameshift, start lost change. 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 frameshift, start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• craniosynostosis 7

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• radioulnar synostosis, nonsyndromic, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• aortic valve disease 2

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital radioulnar synostosis

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 103 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5	c.1_5delATGTT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1024_1028delATGTT		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3	n.1024_1028delATGTT		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.1_5delATGTT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.1_5delATGTT		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.183_187delATGTT		non_coding_transcript_exon_variant	Exon 1 of 1	6
SMAD6	ENST00000557916.5	n.-1_4delTATGT		upstream_gene_variant		1		ENSP00000452955.1

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

SMAD6-related disorder Uncertain:1

Sep 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMAD6 c.1_5del5 variant is predicted to disrupt the translation initiation site (Start Loss). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, different start loss variants have been reported in individuals with craniosynostosis or radioulnar synostosis (p.Met1Arg at Timberlake et al. 2017. PubMed ID: 28808027; p.Met1Thr at Shen et al. 2022. PubMed ID: 34953066). At this time, the clinical significance of the c.1_5del variant found in this patient is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

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

Other links and lift over

hg19: chr15-66995595;