rs17228212

Variant names:

• chr15-67166301-T-C
• rs17228212
• NM_005902.4:c.533-478T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-67166301-T-C
• chr15-67166301-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005902.4(SMAD3):​c.533-478T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 377,908 control chromosomes in the GnomAD database, including 12,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3795 hom., cov: 33)
  • Exomes 𝑓: 0.26 (8692 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0370
• Publications: 75 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-67166301-T-C is Benign according to our data. Variant chr15-67166301-T-C is described in ClinVar as Benign. ClinVar VariationId is 1272319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.533-478T>C		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.533-478T>C		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.401-478T>C		intron	N/A	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.533-478T>C		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.401-478T>C		intron	N/A	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.218-478T>C		intron	N/A	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31468 AN: 152068 Hom.: 3795 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.259 AC: 58365 AN: 225722 Hom.: 8692 AF XY: 0.259 AC XY: 28573 AN XY: 110334

African (AFR) AF: 0.102 AC: 648 AN: 6352

American (AMR) AF: 0.150 AC: 658 AN: 4390

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 400 AN: 2570

East Asian (EAS) AF: 0.00468 AC: 27 AN: 5772

South Asian (SAS) AF: 0.155 AC: 1516 AN: 9786

European-Finnish (FIN) AF: 0.186 AC: 332 AN: 1788

Middle Eastern (MID) AF: 0.213 AC: 122 AN: 574

European-Non Finnish (NFE) AF: 0.283 AC: 52628 AN: 185928

Other (OTH) AF: 0.238 AC: 2034 AN: 8562

GnomAD4 genome AF: 0.207 AC: 31473 AN: 152186 Hom.: 3795 Cov.: 33 AF XY: 0.199 AC XY: 14786 AN XY: 74384

African (AFR) AF: 0.125 AC: 5207 AN: 41540

American (AMR) AF: 0.164 AC: 2503 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5176

South Asian (SAS) AF: 0.147 AC: 708 AN: 4816

European-Finnish (FIN) AF: 0.205 AC: 2178 AN: 10604

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19535 AN: 67974

Other (OTH) AF: 0.193 AC: 408 AN: 2114

Alfa AF: 0.250 Hom.: 16006

Bravo AF: 0.199

Asia WGS AF: 0.0750 AC: 265 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Coronary artery disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.52
PhyloP100		0.037
PromoterAI		0.0046	Neutral
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: rs17228212; hg19: chr15-67458639;