chr15-66703493-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005585.5(SMAD6):c.235G>T(p.Gly79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,228,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G79G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.934

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19710353).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.235G>T	p.Gly79Cys	missense	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1258G>T		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.235G>T	p.Gly79Cys	missense	Exon 1 of 4	ENSP00000288840.5
SMAD6	ENST00000557916.5	TSL:1	n.235G>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1
SMAD6	ENST00000612349.1	TSL:6	n.417G>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151328

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.28e-7

AC:

AN:

1077250

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

509706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22296

American (AMR)

AF:

0.00

AC:

AN:

7906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13602

East Asian (EAS)

AF:

0.00

AC:

AN:

25218

South Asian (SAS)

AF:

0.00

AC:

AN:

19582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2834

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

914176

Other (OTH)

AF:

0.00

AC:

AN:

42660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

AF:

0.0000198

AC:

AN:

151328

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73906

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41322

American (AMR)

AF:

0.00

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67762

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aortic valve disease 2

Uncertain:1

Jun 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 79 of the SMAD6 protein (p.Gly79Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 471753). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.93

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.24

REVEL

Benign

0.11

Sift

Benign

0.096

Sift4G

Benign

0.19

Polyphen

0.40

Vest4

0.16

MutPred

0.29

Loss of relative solvent accessibility (P = 0.0071)

MVP

0.68

MPC

1.2

ClinPred

0.19

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.11

gMVP

0.21

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over