dbSNP rs7182227: SMAD6:c.952+24585C>T (chr15-66741083-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_005585.5(SMAD6):c.952+24585C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,284 control chromosomes in the GnomAD database, including 1,397 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1397 hom., cov: 33)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

SMAD6
NM_005585.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.801

Publications

3 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:

ENSG00000274995 (HGNC:):

ENSG00000274995 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD6	NM_005585.5 link	c.952+24585C>T	intron_variant	Intron 3 of 3	ENST00000288840.10	NP_005576.3	O43541-1
SMAD6	NR_027654.2 link	n.2107+23943C>T	intron_variant	Intron 4 of 4
SMAD6	XM_011521561.3 link	c.169+24585C>T	intron_variant	Intron 3 of 3		XP_011519863.1	O43541-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAD6	ENST00000288840.10 link	c.952+24585C>T	intron_variant	Intron 3 of 3	1	NM_005585.5	ENSP00000288840.5	O43541-1
SMAD6	ENST00000557916.5 link	n.*67+23943C>T	intron_variant	Intron 4 of 4	1		ENSP00000452955.1	O43541-4
ENSG00000274995	ENST00000612806.1 link	n.639C>T	non_coding_transcript_exon_variant	Exon 1 of 1	6
SMAD6	ENST00000559931.5 link	n.*67+23943C>T	intron_variant	Intron 3 of 3	3		ENSP00000453446.1	H0YM33

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18415

AN:

152158

Hom.:

1393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0522

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.0926

Gnomad SAS

AF:

0.0881

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.131

GnomAD4 exome

AF:

0.125

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.121

AC:

18424

AN:

152276

Hom.:

1397

Cov.:

AF XY:

0.123

AC XY:

9123

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0521

AC:

2165

AN:

41560

American (AMR)

AF:

0.239

AC:

3655

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

375

AN:

3466

East Asian (EAS)

AF:

0.0928

AC:

482

AN:

5192

South Asian (SAS)

AF:

0.0883

AC:

426

AN:

4822

European-Finnish (FIN)

AF:

0.133

AC:

1416

AN:

10612

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9414

AN:

68018

Other (OTH)

AF:

0.130

AC:

275

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

832

1664

2496

3328

4160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.131

Hom.:

638

Bravo

AF:

0.127

Asia WGS

AF:

0.0690

AC:

240

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.80

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over