15-67175169-T-C

Variant names:

• chr15-67175169-T-C
• rs12913547
• NM_005902.4:c.658+4565T>C

Variant summary

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

The NM_005902.4(SMAD3):​c.658+4565T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,118 control chromosomes in the GnomAD database, including 5,158 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 0.26 (5158 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 40 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.658+4565T>C		intron_variant	Intron 5 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.658+4565T>C		intron_variant	Intron 5 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38850 AN: 152000 Hom.: 5147 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.256 AC: 38887 AN: 152118 Hom.: 5158 Cov.: 33 AF XY: 0.262 AC XY: 19502 AN XY: 74350

African (AFR) AF: 0.268 AC: 11099 AN: 41486

American (AMR) AF: 0.277 AC: 4236 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1155 AN: 3472

East Asian (EAS) AF: 0.398 AC: 2056 AN: 5162

South Asian (SAS) AF: 0.364 AC: 1750 AN: 4810

European-Finnish (FIN) AF: 0.291 AC: 3077 AN: 10582

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14642 AN: 67994

Other (OTH) AF: 0.289 AC: 611 AN: 2112

Alfa AF: 0.233 Hom.: 13104

Bravo AF: 0.257

Asia WGS AF: 0.365 AC: 1271 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.80
PhyloP100		-1.2
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: rs12913547; hg19: chr15-67467507; COSMIC: COSV107381608; COSMIC: COSV107381608;