rs756752655

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_005585.5(SMAD6):c.173C>G(p.Ser58Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,292,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. S58P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

SMAD6
NM_005585.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.644

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):

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14243111).

BP6

Variant 15-66703431-C-G is Benign according to our data. Variant chr15-66703431-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 571213.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/151654) while in subpopulation NFE AF = 0.000501 (34/67898). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD6	NM_005585.5	MANE Select	c.173C>G	p.Ser58Cys	missense	Exon 1 of 4	NP_005576.3
	SMAD6	NR_027654.2		n.1196C>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMAD6	ENST00000288840.10	TSL:1 MANE Select	c.173C>G	p.Ser58Cys	missense	Exon 1 of 4	ENSP00000288840.5
SMAD6	ENST00000557916.5	TSL:1	n.173C>G		non_coding_transcript_exon	Exon 1 of 5	ENSP00000452955.1
SMAD6	ENST00000612349.1	TSL:6	n.355C>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

151654

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.000501

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000388

AC:

AN:

12886

AF XY:

0.000311

show subpopulations

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:

0.000421

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000206

AC:

235

AN:

1141042

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

116

AN XY:

547286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23088

American (AMR)

AF:

0.00

AC:

AN:

8670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14946

East Asian (EAS)

AF:

0.00

AC:

AN:

26918

South Asian (SAS)

AF:

0.00

AC:

AN:

32102

European-Finnish (FIN)

AF:

0.000428

AC:

AN:

37422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3038

European-Non Finnish (NFE)

AF:

0.000225

AC:

214

AN:

949350

Other (OTH)

AF:

0.000110

AC:

AN:

45508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000237

AC:

AN:

151654

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41332

American (AMR)

AF:

0.0000657

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000501

AC:

AN:

67898

Other (OTH)

AF:

0.000481

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000265

Hom.:

Bravo

AF:

0.000253

ExAC

AF:

0.000112

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aortic valve disease 2 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.31

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.90

PhyloP100

0.64

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.27

REVEL

Benign

0.12

Sift

Benign

0.080

Sift4G

Benign

0.12

Polyphen

0.70

Vest4

0.084

MutPred

0.31

Loss of phosphorylation at S58 (P = 0.0059)

MVP

0.57

MPC

1.1

ClinPred

0.069

GERP RS

2.6

Varity_R

0.069

gMVP

0.38

Mutation Taster

=89/11

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over