Genetic Variant SMAD3:c.206+21911C>T (chr15-67088271-C-T) – 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.206+21911C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 151,984 control chromosomes in the GnomAD database, including 14,918 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 0.43 ( 14918 hom., cov: 31)

Consequence

SMAD3
NM_005902.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.05

Publications

12 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:

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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=-0.95).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.206+21911C>T	intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0
SMAD3	NM_001407011.1 link	c.206+21911C>T	intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1 link	c.206+21911C>T	intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1 link	c.206+21911C>T	intron_variant	Intron 1 of 7		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 link	c.206+21911C>T		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.431

AC:

65526

AN:

151864

Hom.:

14928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.548

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.503

Gnomad EAS

AF:

0.396

Gnomad SAS

AF:

0.655

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.497

Gnomad OTH

AF:

0.446

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.431

AC:

65532

AN:

151984

Hom.:

14918

Cov.:

AF XY:

0.434

AC XY:

32238

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.292

AC:

12116

AN:

41424

American (AMR)

AF:

0.357

AC:

5454

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

1746

AN:

3472

East Asian (EAS)

AF:

0.396

AC:

2037

AN:

5148

South Asian (SAS)

AF:

0.654

AC:

3157

AN:

4824

European-Finnish (FIN)

AF:

0.531

AC:

5607

AN:

10554

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.497

AC:

33806

AN:

67976

Other (OTH)

AF:

0.444

AC:

938

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1867

3733

5600

7466

9333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.464

Hom.:

24021

Bravo

AF:

0.405

Asia WGS

AF:

0.471

AC:

1638

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.0040

(source)

DANN

Benign

0.61

PhyloP100

-5.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over