15-66703260-T-G

Variant names:

• chr15-66703260-T-G
• rs1409145798
• NM_005585.5:c.2T>G

Variant summary

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

The NM_005585.5(SMAD6):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000768 in 1,301,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SMAD6 NM_005585.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.53
• Publications: 1 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):

• syndromic craniosynostosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• craniosynostosis 7

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

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

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 93 codons. Genomic position: 66703535. Lost 0.186 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005585.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1025T>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 4	ENSP00000288840.5	O43541-1
	SMAD6	ENST00000557916.5	TSL:1	n.2T>G		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
	SMAD6	ENST00000966143.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.68e-7 AC: 1 AN: 1301556 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 642230

African (AFR) AF: 0.00 AC: 0 AN: 25756

American (AMR) AF: 0.00 AC: 0 AN: 21378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22074

East Asian (EAS) AF: 0.00 AC: 0 AN: 28576

South Asian (SAS) AF: 0.00 AC: 0 AN: 67472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3932

European-Non Finnish (NFE) AF: 9.68e-7 AC: 1 AN: 1033266

Other (OTH) AF: 0.00 AC: 0 AN: 52732

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic valve disease 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.27	D
PhyloP100		4.5
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.97		Gain of methylation at M1 (P = 0.0051)
MVP		0.85
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		0.76
Mutation Taster		=9/191	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1409145798; hg19: chr15-66995598;