rs566777509

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1

The NM_005585.5(SMAD6):c.290G>A(p.Gly97Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,221,858 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G97G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 2.99

Publications

2 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11071277).

BP6

Variant 15-66703548-G-A is Benign according to our data. Variant chr15-66703548-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 405513.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 = 0.000806 (122/151318) while in subpopulation AFR AF = 0.0028 (116/41446). AF 95% confidence interval is 0.00238. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.290G>A	p.Gly97Glu	missense	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1313G>A		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.290G>A	p.Gly97Glu	missense	Exon 1 of 4	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5	TSL:1	n.290G>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1	O43541-4
SMAD6	ENST00000966143.1		c.290G>A	p.Gly97Glu	missense	Exon 1 of 3	ENSP00000636202.1

Frequencies

GnomAD3 genomes

AF:

0.000807

AC:

122

AN:

151210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

4228

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.0000607

AC:

AN:

1070540

Hom.:

Cov.:

AF XY:

0.0000651

AC XY:

AN XY:

506754

show subpopulations

African (AFR)

AF:

0.00258

AC:

AN:

22098

American (AMR)

AF:

0.000258

AC:

AN:

7740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13308

East Asian (EAS)

AF:

0.00

AC:

AN:

24814

South Asian (SAS)

AF:

0.00

AC:

AN:

19536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26590

Middle Eastern (MID)

AF:

0.000711

AC:

AN:

2812

European-Non Finnish (NFE)

AF:

0.00000219

AC:

AN:

911396

Other (OTH)

AF:

0.0000473

AC:

AN:

42246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000806

AC:

122

AN:

151318

Hom.:

Cov.:

AF XY:

0.000703

AC XY:

AN XY:

73960

show subpopulations

African (AFR)

AF:

0.00280

AC:

116

AN:

41446

American (AMR)

AF:

0.000132

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67684

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000427

Hom.:

Bravo

AF:

0.000827

ExAC

AF:

0.0000715

AC:

Asia WGS

AF:

0.000312

AC:

AN:

3218

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aortic valve disease 2 (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.6

PhyloP100

3.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.41

REVEL

Benign

0.26

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.012

Polyphen

0.51

Vest4

0.039

MVP

0.62

MPC

1.5

ClinPred

0.76

GERP RS

4.1

Varity_R

0.22

gMVP

0.19

Mutation Taster

=80/20

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

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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