dbSNP rs36222034: SMAD3:c.-110+1396G>A (chr15-67065340-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000559460.6(SMAD3):c.-110+1396G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 151,966 control chromosomes in the GnomAD database, including 1,147 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 ( 1146 hom., cov: 32)

Exomes 𝑓: 0.12 ( 1 hom. )

Consequence

SMAD3
ENST00000559460.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0470

Publications

4 publications found

Variant links:

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 links:

SMAD3-DT (HGNC:56759): (SMAD3 divergent transcript)

SMAD3-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000559460.6 link	c.-110+1396G>A		intron_variant	Intron 1 of 8	4		ENSP00000453082.2		H0YL71
SMAD3-DT	ENST00000636067.1 link	n.-72C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17629

AN:

151728

Hom.:

1147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0671

Gnomad AMI

AF:

0.0604

Gnomad AMR

AF:

0.0987

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.163

Gnomad MID

AF:

0.0860

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.112

GnomAD4 exome

AF:

0.119

AC:

AN:

118

Hom.:

AF XY:

0.140

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.167

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.106

AC:

AN:

104

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.116

AC:

17621

AN:

151848

Hom.:

1146

Cov.:

AF XY:

0.120

AC XY:

8884

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.0669

AC:

2777

AN:

41522

American (AMR)

AF:

0.0987

AC:

1508

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

497

AN:

3468

East Asian (EAS)

AF:

0.147

AC:

750

AN:

5106

South Asian (SAS)

AF:

0.219

AC:

1053

AN:

4814

European-Finnish (FIN)

AF:

0.163

AC:

1713

AN:

10504

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.133

AC:

9007

AN:

67838

Other (OTH)

AF:

0.111

AC:

233

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

783

1566

2348

3131

3914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<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:

0.127

Hom.:

162

Bravo

AF:

0.106

Asia WGS

AF:

0.138

AC:

478

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.047

PromoterAI

0.074

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over