rs2289263

Positions:

• chr15-67146869-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(SMAD3):​c.207-18026T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 151,828 control chromosomes in the GnomAD database, including 14,659 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 0.43 (14648 hom., cov: 31)
  • Exomes 𝑓: 0.53 (11 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.954

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-AS1 (HGNC:56692): (SMAD3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-18026T>G		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-18026T>G		intron_variant		1	NM_005902.4	ENSP00000332973	P1
SMAD3-AS1	ENST00000558463.1	n.28+43A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65745 AN: 151648 Hom.: 14646 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.530 AC: 35 AN: 66 Hom.: 11 Cov.: 0 AF XY: 0.537 AC XY: 29 AN XY: 54

Gnomad4 AFR exome AF: 0.250

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.433 AC: 65786 AN: 151762 Hom.: 14648 Cov.: 31 AF XY: 0.439 AC XY: 32525 AN XY: 74164

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.466

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.467

Alfa AF: 0.467 Hom.: 20726

Bravo AF: 0.418

Asia WGS AF: 0.435 AC: 1513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.6
DANN	Benign	0.79

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: rs2289263; hg19: chr15-67439207;