rs371330988

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_005585.5(SMAD6):c.336C>A(p.Gly112Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.000226 in 1,227,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.11

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 15-66703594-C-A is Benign according to our data. Variant chr15-66703594-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 471757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (174/151184) while in subpopulation AFR AF = 0.00398 (165/41440). AF 95% confidence interval is 0.00348. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMAD6	NM_005585.5 link	c.336C>A	p.Gly112Gly	synonymous_variant	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2 link	n.1359C>A		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3 link	n.1359C>A		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMAD6	ENST00000288840.10 link	c.336C>A	p.Gly112Gly	synonymous_variant	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5 link	n.336C>A		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1 link	n.518C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

174

AN:

151076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00399

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

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:

0.00

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.000323

AC:

AN:

9292

AF XY:

0.000200

show subpopulations

Gnomad AFR exome

AF:

0.00625

Gnomad AMR exome

AF:

0.00

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:

0.0000966

AC:

104

AN:

1076764

Hom.:

Cov.:

AF XY:

0.0000783

AC XY:

AN XY:

510626

show subpopulations

African (AFR)

AF:

0.00417

AC:

AN:

22276

American (AMR)

AF:

0.000370

AC:

AN:

8118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13274

East Asian (EAS)

AF:

0.00

AC:

AN:

25150

South Asian (SAS)

AF:

0.00

AC:

AN:

19764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2834

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

914468

Other (OTH)

AF:

0.000189

AC:

AN:

42390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.00115

AC:

174

AN:

151184

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.00398

AC:

165

AN:

41440

American (AMR)

AF:

0.000263

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67618

Other (OTH)

AF:

0.00239

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000208

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SMAD6-related disorder

Benign:1

Mar 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Feb 20, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aortic valve disease 2

Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aortic valve disease 2;C4479496:Craniosynostosis 7

Benign:1

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over