rs12324036

Variant names:

• chr15-67085152-T-C
• rs12324036
• NM_005902.4:c.206+18792T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-67085152-T-C
• chr15-67085152-T-G

Variant summary

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

The NM_005902.4(SMAD3):​c.206+18792T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,008 control chromosomes in the GnomAD database, including 22,918 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 0.55 (22918 hom., cov: 31)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 9 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 (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.206+18792T>C		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.206+18792T>C		intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1	c.206+18792T>C		intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1	c.206+18792T>C		intron_variant	Intron 1 of 7		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+18792T>C		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83021 AN: 151890 Hom.: 22909 Cov.: 31

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.546 AC: 83056 AN: 152008 Hom.: 22918 Cov.: 31 AF XY: 0.551 AC XY: 40950 AN XY: 74292

African (AFR) AF: 0.485 AC: 20095 AN: 41450

American (AMR) AF: 0.583 AC: 8910 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1916 AN: 3470

East Asian (EAS) AF: 0.625 AC: 3234 AN: 5174

South Asian (SAS) AF: 0.728 AC: 3502 AN: 4812

European-Finnish (FIN) AF: 0.562 AC: 5942 AN: 10564

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37491 AN: 67946

Other (OTH) AF: 0.559 AC: 1179 AN: 2110

Alfa AF: 0.548 Hom.: 3267

Bravo AF: 0.543

Asia WGS AF: 0.603 AC: 2096 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	0.15
DANN	Benign	0.32
PhyloP100		-1.5
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: rs12324036; hg19: chr15-67377490;