15-66703260-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005585.5(SMAD6):c.2T>A(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, single submitter U:1
• Conservation: PhyloP100: 4.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD6	NM_005585.5	c.2T>A	p.Met1?	start_lost	1/4	ENST00000288840.10
SMAD6	NR_027654.2	n.1025T>A		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1025T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD6	ENST00000288840.10	c.2T>A	p.Met1?	start_lost	1/4	1	NM_005585.5	P1
SMAD6	ENST00000557916.5	c.2T>A	p.Met1?	start_lost, NMD_transcript_variant	1/5	1
SMAD6	ENST00000612349.1	n.184T>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.68e-7 AC: 1 AN: 1301556 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 642230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Invitae

Oct 17, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Disruption of the initiator codon has been observed in individual(s) with craniosynostosis (PMID: 28808027). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SMAD6 mRNA. The next in-frame methionine is located at codon 93. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.90
MutPred		0.97		Loss of stability (P = 0.0027);
MVP		0.84
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -4

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: chr15-66995598;