rs769605183

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BS1_Supporting

The NM_005585.5(SMAD6):c.79_84delAGCGGC(p.Ser27_Gly28del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000553 in 1,485,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S27S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.63

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):

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: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005585.5

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000559 (85/152132) while in subpopulation AMR AF = 0.00131 (20/15300). AF 95% confidence interval is 0.000866. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMAD6	NM_005585.5 link	c.79_84delAGCGGC	p.Ser27_Gly28del	conservative_inframe_deletion	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2 link	n.1102_1107delAGCGGC		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3 link	n.1102_1107delAGCGGC		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.79_84delAGCGGC	p.Ser27_Gly28del	conservative_inframe_deletion	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5 link	n.79_84delAGCGGC		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1 link	n.261_266delAGCGGC		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000247

AC:

AN:

92970

AF XY:

0.000173

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.000838

GnomAD4 exome

AF:

0.000553

AC:

737

AN:

1333528

Hom.:

AF XY:

0.000564

AC XY:

371

AN XY:

657798

show subpopulations

African (AFR)

AF:

0.000112

AC:

AN:

26690

American (AMR)

AF:

0.000675

AC:

AN:

26678

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

23298

East Asian (EAS)

AF:

0.00

AC:

AN:

28488

South Asian (SAS)

AF:

0.0000275

AC:

AN:

72838

European-Finnish (FIN)

AF:

0.0000850

AC:

AN:

47070

Middle Eastern (MID)

AF:

0.000236

AC:

AN:

4234

European-Non Finnish (NFE)

AF:

0.000644

AC:

676

AN:

1049568

Other (OTH)

AF:

0.000494

AC:

AN:

54664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000559

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41536

American (AMR)

AF:

0.00131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000854

AC:

AN:

67954

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000978

Hom.:

Bravo

AF:

0.000518

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Dec 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMAD6 c.79_84delAGCGGC (p.Ser27_Gly28del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.00025 in 92970 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD6 causing Aortic Valve Disease phenotype (3.1e-05), strongly suggesting that the variant is benign. c.79_84delAGCGGC has been reported in the literature in individuals affected with Aortic Valve Disease (Gillis_2017). This report does not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28659821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jan 29, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a patient with bicuspid aortic valve who also harbors a variant in the NOTCH1 gene (PMID: 28659821); Identified in a patient with craniosynostosis; however, clinical details were not provided and segregation analysis was not performed (PMID: 32499606); In-frame deletion of two amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30848080, 28659821, 32499606)

Aortic valve disease 2

Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.79_84del, results in the deletion of 2 amino acid(s) of the SMAD6 protein (p.Ser27_Gly28del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769605183, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with SMAD6-related conditions (PMID: 28659821, 32499606). ClinVar contains an entry for this variant (Variation ID: 471762). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Aortic valve disease 2;C4479496:Craniosynostosis 7

Uncertain:1

Oct 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=148/52

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over