rs731874

Variant names:

• chr15-67154493-G-A
• rs731874
• NM_005902.4:c.207-10402G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(SMAD3):​c.207-10402G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,120 control chromosomes in the GnomAD database, including 3,514 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 0.19 (3514 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-10402G>A		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-10402G>A		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29240 AN: 152002 Hom.: 3514 Cov.: 33

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.192 AC: 29244 AN: 152120 Hom.: 3514 Cov.: 33 AF XY: 0.184 AC XY: 13704 AN XY: 74366

African (AFR) AF: 0.0841 AC: 3489 AN: 41500

American (AMR) AF: 0.156 AC: 2377 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5184

South Asian (SAS) AF: 0.146 AC: 706 AN: 4820

European-Finnish (FIN) AF: 0.198 AC: 2090 AN: 10568

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19278 AN: 67980

Other (OTH) AF: 0.180 AC: 380 AN: 2108

Alfa AF: 0.249 Hom.: 8803

Bravo AF: 0.182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.57
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs731874; hg19: chr15-67446831;