Genetic Variant SMAD3:c.206+25452C>T (chr15-67091812-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+25452C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,914 control chromosomes in the GnomAD database, including 17,024 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 0.45 ( 17024 hom., cov: 32)

Consequence

SMAD3
NM_005902.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.347

Publications

11 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=-0.79).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.206+25452C>T	intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0
SMAD3	NM_001407011.1 link	c.206+25452C>T	intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1 link	c.206+25452C>T	intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1 link	c.206+25452C>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+25452C>T		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68421

AN:

151796

Hom.:

17026

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.489

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.700

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.564

Gnomad NFE

AF:

0.517

Gnomad OTH

AF:

0.484

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

GnomAD4 genome

AF:

0.450

AC:

68429

AN:

151914

Hom.:

17024

Cov.:

AF XY:

0.459

AC XY:

34112

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.225

AC:

9321

AN:

41390

American (AMR)

AF:

0.537

AC:

8205

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

1697

AN:

3470

East Asian (EAS)

AF:

0.605

AC:

3121

AN:

5162

South Asian (SAS)

AF:

0.699

AC:

3362

AN:

4810

European-Finnish (FIN)

AF:

0.551

AC:

5810

AN:

10536

Middle Eastern (MID)

AF:

0.562

AC:

163

AN:

290

European-Non Finnish (NFE)

AF:

0.517

AC:

35143

AN:

67960

Other (OTH)

AF:

0.481

AC:

1018

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1757

3515

5272

7030

8787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

640

1280

1920

2560

3200

<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:

0.494

Hom.:

24020

Bravo

AF:

0.436

Asia WGS

AF:

0.570

AC:

1982

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.9

(source)

DANN

Benign

0.73

PhyloP100

0.35

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