rs1085307496

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001145102.2(SMAD3):c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SMAD3
NM_001145102.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 7.72

Publications

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

SMAD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 15-67164956-C-T is Pathogenic according to our data. Variant chr15-67164956-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426202.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145102.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMAD3	NM_005902.4	MANE Select	c.268C>T	p.Arg90Cys	missense	Exon 2 of 9	NP_005893.1	P84022-1
SMAD3	NM_001145102.2		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001138574.1	P84022-3
SMAD3	NM_001407016.1		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001393945.1	P84022-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMAD3	ENST00000540846.6	TSL:1	c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000437757.2	P84022-3
SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.268C>T	p.Arg90Cys	missense	Exon 2 of 9	ENSP00000332973.4	P84022-1
SMAD3	ENST00000439724.7	TSL:1	c.136C>T	p.Arg46Cys	missense	Exon 2 of 9	ENSP00000401133.3	P84022-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251404

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aneurysm-osteoarthritis syndrome (3)

Familial thoracic aortic aneurysm and aortic dissection (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.3

PhyloP100

7.7

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.92

Loss of MoRF binding (P = 0.0099)

MVP

0.96

MPC

2.0

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.94

Mutation Taster

=196/104

polymorphism

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over