Genetic Variant SMAD3:c.206+6924A>G (chr15-67073284-A-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.206+6924A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 152,038 control chromosomes in the GnomAD database, including 16,563 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 0.46 ( 16563 hom., cov: 33)

Consequence

SMAD3
NM_005902.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.329

Publications

21 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=-0.9).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.206+6924A>G	intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0
SMAD3	NM_001407011.1 link	c.206+6924A>G	intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1 link	c.206+6924A>G	intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1 link	c.206+6924A>G	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+6924A>G		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70250

AN:

151920

Hom.:

16542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.431

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.369

Gnomad ASJ

AF:

0.502

Gnomad EAS

AF:

0.540

Gnomad SAS

AF:

0.659

Gnomad FIN

AF:

0.527

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.473

Gnomad OTH

AF:

0.449

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

GnomAD4 genome

AF:

0.462

AC:

70312

AN:

152038

Hom.:

16563

Cov.:

AF XY:

0.469

AC XY:

34831

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.431

AC:

17859

AN:

41428

American (AMR)

AF:

0.368

AC:

5629

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.502

AC:

1739

AN:

3466

East Asian (EAS)

AF:

0.540

AC:

2797

AN:

5176

South Asian (SAS)

AF:

0.657

AC:

3166

AN:

4818

European-Finnish (FIN)

AF:

0.527

AC:

5573

AN:

10570

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.473

AC:

32162

AN:

67982

Other (OTH)

AF:

0.453

AC:

954

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1942

3884

5825

7767

9709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.465

Hom.:

43242

Bravo

AF:

0.439

Asia WGS

AF:

0.566

AC:

1966

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.8

(source)

DANN

Benign

0.60

PhyloP100

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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.

15-67073284-A-G

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