rs17228212

Positions:

• chr15-67166301-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.533-478T>C		intron_variant		ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.533-478T>C		intron_variant		1	NM_005902.4	P1

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

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.00468

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.238

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

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.193

Alfa AF: 0.263 Hom.: 10531

Bravo AF: 0.199

Asia WGS AF: 0.0750 AC: 265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coronary artery disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Rasad Genetic Department, Rasad Pathobiology and Genetic Laboratory

May 12, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.52

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: rs17228212; hg19: chr15-67458639;