rs144415105

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005585.5(SMAD6):c.711C>T(p.His237His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,448,960 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 203 hom. )

Consequence

SMAD6
NM_005585.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.97

Publications

1 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):

syndromic craniosynostosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
craniosynostosis 7
Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
radioulnar synostosis, nonsyndromic, susceptibility to
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics
aortic valve disease 2
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 15-66703969-C-T is Benign according to our data. Variant chr15-66703969-C-T is described in ClinVar as Benign. ClinVar VariationId is 413445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.711C>T	p.His237His	synonymous	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1734C>T		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.711C>T	p.His237His	synonymous	Exon 1 of 4	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5	TSL:1	n.711C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
SMAD6	ENST00000966143.1		c.711C>T	p.His237His	synonymous	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes

AF:

0.00733

AC:

1115

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0767

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.000757

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00959

GnomAD2 exomes

AF:

0.0120

AC:

904

AN:

75040

AF XY:

0.0119

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.000461

Gnomad EAS exome

AF:

0.0758

Gnomad FIN exome

AF:

0.000850

Gnomad NFE exome

AF:

0.00505

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00838

AC:

10862

AN:

1296830

Hom.:

203

Cov.:

AF XY:

0.00863

AC XY:

5518

AN XY:

639630

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

26618

American (AMR)

AF:

0.0131

AC:

328

AN:

25024

Ashkenazi Jewish (ASJ)

AF:

0.000569

AC:

AN:

22858

East Asian (EAS)

AF:

0.102

AC:

2852

AN:

27888

South Asian (SAS)

AF:

0.0220

AC:

1540

AN:

70068

European-Finnish (FIN)

AF:

0.00106

AC:

AN:

32152

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

3904

European-Non Finnish (NFE)

AF:

0.00539

AC:

5584

AN:

1035096

Other (OTH)

AF:

0.00870

AC:

463

AN:

53222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

641

1281

1922

2562

3203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00731

AC:

1112

AN:

152130

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

603

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41556

American (AMR)

AF:

0.0114

AC:

175

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0765

AC:

394

AN:

5148

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4830

European-Finnish (FIN)

AF:

0.000757

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00478

AC:

325

AN:

67954

Other (OTH)

AF:

0.00949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00492

Hom.:

Bravo

AF:

0.00760

Asia WGS

AF:

0.0450

AC:

156

AN:

3466

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Aortic valve disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over