rs80232004

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_005585.5(SMAD6):c.362G>A(p.Cys121Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,231,328 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C121W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.86

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004272312).

BP6

Variant 15-66703620-G-A is Benign according to our data. Variant chr15-66703620-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436796.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00123 (186/151118) while in subpopulation EAS AF = 0.0134 (69/5138). AF 95% confidence interval is 0.0109. There are 1 homozygotes in GnomAd4. There are 106 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.362G>A	p.Cys121Tyr	missense_variant	Exon 1 of 4	ENST00000288840.10	NP_005576.3
SMAD6	NR_027654.2 link	n.1385G>A		non_coding_transcript_exon_variant	Exon 1 of 5
SMAD6	XR_931827.3 link	n.1385G>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.362G>A	p.Cys121Tyr	missense_variant	Exon 1 of 4	1	NM_005585.5	ENSP00000288840.5
SMAD6	ENST00000557916.5 link	n.362G>A		non_coding_transcript_exon_variant	Exon 1 of 5	1		ENSP00000452955.1
SMAD6	ENST00000612349.1 link	n.544G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

188

AN:

151010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00705

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0136

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000798

AC:

AN:

8770

AF XY:

0.000853

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00645

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.000383

AC:

414

AN:

1080210

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

177

AN XY:

513618

show subpopulations

African (AFR)

AF:

0.0000451

AC:

AN:

22162

American (AMR)

AF:

0.00817

AC:

AN:

7956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13146

East Asian (EAS)

AF:

0.0130

AC:

325

AN:

25050

South Asian (SAS)

AF:

0.000202

AC:

AN:

19836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2856

European-Non Finnish (NFE)

AF:

0.00000327

AC:

AN:

917266

Other (OTH)

AF:

0.000377

AC:

AN:

42458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

103

129

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:

0.00123

AC:

186

AN:

151118

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

106

AN XY:

73880

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41438

American (AMR)

AF:

0.00704

AC:

107

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.0134

AC:

AN:

5138

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67606

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000393

Hom.:

Bravo

AF:

0.00179

ExAC

AF:

0.000852

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Aortic valve disease 2

Uncertain:1Benign:1

May 31, 2019

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Aug 19, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SMAD6 c.362G>A (p.Cys121Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 1231328 control chromosomes, predominantly at a frequency of 0.013 within the Latino subpopulation in the gnomAD database v4. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 415.99 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.362G>A in individuals affected with Aortic Valve Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 436796). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.6

PhyloP100

2.9

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-0.95

REVEL

Uncertain

0.48

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.036

Polyphen

0.98

Vest4

0.14

MVP

0.81

MPC

2.6

ClinPred

0.18

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.46

gMVP

0.51

Mutation Taster

=63/37

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over