15-66704072-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P272L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.51

Publications

0 publications found

Variant links:

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

SMAD6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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 link	c.814C>T	p.Pro272Ser	missense_variant	Exon 1 of 4	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 link	n.1837C>T		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3 link	n.1837C>T		non_coding_transcript_exon_variant	Exon 1 of 4
SMAD6	XM_011521561.3 link	c.-4633C>T		upstream_gene_variant			XP_011519863.1	O43541-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD6	ENST00000288840.10 link	c.814C>T	p.Pro272Ser	missense_variant	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 link	n.814C>T		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1	O43541-4
SMAD6	ENST00000612349.1 link	n.996C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000322

AC:

AN:

93080

AF XY:

0.0000366

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000300

AC:

AN:

1331632

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

659152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27028

American (AMR)

AF:

0.000139

AC:

AN:

28798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23340

East Asian (EAS)

AF:

0.00

AC:

AN:

29462

South Asian (SAS)

AF:

0.00

AC:

AN:

73914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057154

Other (OTH)

AF:

0.00

AC:

AN:

54916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000192

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 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"). 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). This variant is present in population databases (rs781458675, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SMAD6-related conditions. ClinVar contains an entry for this variant (Variation ID: 471763). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.2

PhyloP100

4.5

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.023

Sift4G

Benign

0.54

Polyphen

1.0

Vest4

0.41

MutPred

0.32

Gain of phosphorylation at P272 (P = 0.0306);

MVP

0.93

MPC

0.89

ClinPred

0.69

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.52

Mutation Taster

=43/57

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over