rs1498506

Variant names:

• chr15-67075296-A-C
• rs1498506
• NM_005902.4:c.206+8936A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-67075296-A-C
• chr15-67075296-A-G
• chr15-67075296-A-T

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+8936A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 151,994 control chromosomes in the GnomAD database, including 16,552 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 0.46 (16552 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.419
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.206+8936A>C		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.206+8936A>C		intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1	c.206+8936A>C		intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1	c.206+8936A>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+8936A>C		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70192 AN: 151876 Hom.: 16531 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.462 AC: 70254 AN: 151994 Hom.: 16552 Cov.: 32 AF XY: 0.468 AC XY: 34805 AN XY: 74292

African (AFR) AF: 0.431 AC: 17868 AN: 41444

American (AMR) AF: 0.367 AC: 5612 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1725 AN: 3470

East Asian (EAS) AF: 0.540 AC: 2795 AN: 5180

South Asian (SAS) AF: 0.657 AC: 3161 AN: 4814

European-Finnish (FIN) AF: 0.527 AC: 5554 AN: 10540

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32148 AN: 67952

Other (OTH) AF: 0.454 AC: 958 AN: 2112

Alfa AF: 0.366 Hom.: 1134

Bravo AF: 0.439

Asia WGS AF: 0.566 AC: 1965 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.79
DANN	Benign	0.74
PhyloP100		-0.42
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: rs1498506; hg19: chr15-67367634;