rs12915039

chr15-67142010-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(SMAD3):c.207-22885A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,070 control chromosomes in the GnomAD database, including 3,959 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 0.21 (3959 hom., cov: 31)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.438

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.207-22885A>C		intron_variant		ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-22885A>C		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32581 AN: 151952 Hom.: 3960 Cov.: 31

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.214 AC: 32579 AN: 152070 Hom.: 3959 Cov.: 31 AF XY: 0.222 AC XY: 16524 AN XY: 74338

Gnomad4 AFR AF: 0.0938

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.235

Alfa AF: 0.234 Hom.: 5692

Bravo AF: 0.204

Asia WGS AF: 0.333 AC: 1158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.8
Dann	Benign	0.66

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

LitVar

Other links and lift over

dbSNP: rs12915039; hg19: chr15-67434348;