chr15-66703257-GTATGT-G

Position:

• chr15-66703257-GTATGT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate 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

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 Pathogenic. Variant got 12 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 23 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_005585.5 (SMAD6) was described as [Pathogenic] in Lovd
• 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.1_5delATGTT	p.Met1fs	frameshift_variant, start_lost	1/4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1024_1028delATGTT		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1024_1028delATGTT		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.1_5delATGTT	p.Met1fs	frameshift_variant, start_lost	1/4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.1_5delATGTT		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.183_187delATGTT		non_coding_transcript_exon_variant	1/1	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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2023

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

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-66995595;