Genetic Variant SMAD3:c.658+3937T>G (chr15-67174541-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005902.4(SMAD3):c.658+3937T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,234 control chromosomes in the GnomAD database, including 58,376 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 0.87 ( 58280 hom., cov: 30)

Exomes 𝑓: 0.90 ( 96 hom. )

Consequence

SMAD3
NM_005902.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26

Publications

14 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 Gene-Disease associations (from GenCC):

aneurysm-osteoarthritis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

SMAD3 links:

Genome browser will be placed here

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=-0.89).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.658+3937T>G		intron_variant	Intron 5 of 8	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 link	c.658+3937T>G		intron_variant	Intron 5 of 8	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.875

AC:

132880

AN:

151876

Hom.:

58233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.860

Gnomad AMI

AF:

0.886

Gnomad AMR

AF:

0.913

Gnomad ASJ

AF:

0.875

Gnomad EAS

AF:

0.763

Gnomad SAS

AF:

0.814

Gnomad FIN

AF:

0.864

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.890

Gnomad OTH

AF:

0.884

GnomAD4 exome

AF:

0.896

AC:

215

AN:

240

Hom.:

Cov.:

AF XY:

0.897

AC XY:

156

AN XY:

174

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.722

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.900

AC:

162

AN:

180

Other (OTH)

AF:

0.875

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.875

AC:

132983

AN:

151994

Hom.:

58280

Cov.:

AF XY:

0.873

AC XY:

64822

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.860

AC:

35632

AN:

41440

American (AMR)

AF:

0.913

AC:

13952

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.875

AC:

3038

AN:

3472

East Asian (EAS)

AF:

0.763

AC:

3923

AN:

5144

South Asian (SAS)

AF:

0.813

AC:

3906

AN:

4802

European-Finnish (FIN)

AF:

0.864

AC:

9125

AN:

10562

Middle Eastern (MID)

AF:

0.891

AC:

262

AN:

294

European-Non Finnish (NFE)

AF:

0.890

AC:

60471

AN:

67974

Other (OTH)

AF:

0.885

AC:

1866

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

821

1641

2462

3282

4103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.885

Hom.:

41514

Bravo

AF:

0.882

Asia WGS

AF:

0.783

AC:

2724

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

6.9

(source)

DANN

Benign

0.58

PhyloP100

1.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over