dbSNP rs36221701: SMAD3-DT:n.1118A>G (chr15-67064151-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000636067.1(SMAD3-DT):n.1118A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,356 control chromosomes in the GnomAD database, including 1,721 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 0.14 ( 1721 hom., cov: 33)

Exomes 𝑓: 0.15 ( 0 hom. )

Consequence

SMAD3-DT
ENST00000636067.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.622

Publications

7 publications found

Variant links:

Genes affected

SMAD3-DT (HGNC:56759): (SMAD3 divergent transcript)

SMAD3-DT links:

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 (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3-DT	NR_135686.1 link	n.32A>G		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3-DT	ENST00000636067.1 link	n.1118A>G		non_coding_transcript_exon_variant	Exon 1 of 3	5
SMAD3	ENST00000559460.6 link	c.-110+207T>C		intron_variant	Intron 1 of 8	4		ENSP00000453082.2		H0YL71

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20696

AN:

152186

Hom.:

1703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0946

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.0884

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.127

GnomAD4 exome

AF:

0.154

AC:

AN:

Hom.:

Cov.:

AF XY:

0.107

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.111

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.136

AC:

20767

AN:

152304

Hom.:

1721

Cov.:

AF XY:

0.137

AC XY:

10171

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.209

AC:

8680

AN:

41560

American (AMR)

AF:

0.0945

AC:

1446

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

401

AN:

3472

East Asian (EAS)

AF:

0.197

AC:

1023

AN:

5190

South Asian (SAS)

AF:

0.187

AC:

902

AN:

4832

European-Finnish (FIN)

AF:

0.0884

AC:

938

AN:

10610

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

7038

AN:

68020

Other (OTH)

AF:

0.132

AC:

279

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

931

1861

2792

3722

4653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

226

452

678

904

1130

<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:

0.0481

Hom.:

Bravo

AF:

0.137

Asia WGS

AF:

0.196

AC:

679

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

6.2

(source)

DANN

Benign

0.75

PhyloP100

-0.62

PromoterAI

0.13

Neutral

(source)

Splicing

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