Genetic Variant SMAD3:c.-240G>A (chr15-67065915-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005902.4(SMAD3):c.-240G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 62,316 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SMAD3
NM_005902.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.403

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD3	NM_005902.4	MANE Select	c.-240G>A	5_prime_UTR	Exon 1 of 9	NP_005893.1	P84022-1
SMAD3	NM_001407011.1		c.-240G>A	5_prime_UTR	Exon 1 of 10	NP_001393940.1	H3BQ00
SMAD3	NM_001407012.1		c.-240G>A	5_prime_UTR	Exon 1 of 8	NP_001393941.1	A0AAQ5BHI7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.-240G>A	5_prime_UTR	Exon 1 of 9	ENSP00000332973.4	P84022-1
SMAD3	ENST00000560424.2	TSL:3	c.-240G>A	5_prime_UTR	Exon 1 of 10	ENSP00000455540.2	H3BQ00
SMAD3	ENST00000559460.6	TSL:4	c.-110+1971G>A	intron	N/A	ENSP00000453082.2	P84022-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000160

AC:

AN:

62316

Hom.:

Cov.:

AF XY:

0.0000332

AC XY:

AN XY:

30092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

2504

American (AMR)

AF:

0.00

AC:

AN:

1766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3568

East Asian (EAS)

AF:

0.00

AC:

AN:

9202

South Asian (SAS)

AF:

0.00

AC:

AN:

588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

616

Middle Eastern (MID)

AF:

0.00276

AC:

AN:

362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

38768

Other (OTH)

AF:

0.00

AC:

AN:

4942

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.8

(source)

DANN

Benign

0.96

PhyloP100

-0.40

PromoterAI

-0.062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over