15-66704072-C-T

Position:

• chr15-66704072-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005585.5(SMAD6):​c.814C>T​(p.Pro272Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000003 in 1,331,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SMAD6 NM_005585.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.51

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.814C>T	p.Pro272Ser	missense_variant	1/4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2	n.1837C>T		non_coding_transcript_exon_variant	1/5
SMAD6	XR_931827.3	n.1837C>T		non_coding_transcript_exon_variant	1/4
SMAD6	XM_011521561.3	c.-4633C>T		upstream_gene_variant			XP_011519863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD6	ENST00000288840.10	c.814C>T	p.Pro272Ser	missense_variant	1/4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5	n.814C>T		non_coding_transcript_exon_variant	1/5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1	n.996C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000322 AC: 3 AN: 93080 Hom.: 0 AF XY: 0.0000366 AC XY: 2 AN XY: 54578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1331632 Hom.: 0 Cov.: 32 AF XY: 0.00000303 AC XY: 2 AN XY: 659152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.0000192 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.814C>T (p.P272S) alteration is located in exon 1 (coding exon 1) of the SMAD6 gene. This alteration results from a C to T substitution at nucleotide position 814, causing the proline (P) at amino acid position 272 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 471763). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. This variant is present in population databases (rs781458675, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 272 of the SMAD6 protein (p.Pro272Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.023	D
Sift4G	Benign	0.54	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.32		Gain of phosphorylation at P272 (P = 0.0306);
MVP		0.93
MPC		0.89
ClinPred		0.69	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs781458675; hg19: chr15-66996410;