rs12901499

Positions:

• chr15-67078107-G-A

Variant summary

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

The NM_005902.4(SMAD3):​c.206+11747G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,116 control chromosomes in the GnomAD database, including 15,936 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 0.45 (15931 hom., cov: 33)
  • Exomes 𝑓: 0.45 (5 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.206+11747G>A		intron_variant		ENST00000327367.9
SMAD3	NM_001407011.1	c.206+11747G>A		intron_variant
SMAD3	NM_001407012.1	c.206+11747G>A		intron_variant
SMAD3	NM_001407013.1	c.206+11747G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+11747G>A		intron_variant		1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68978 AN: 151956 Hom.: 15909 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.452 AC: 19 AN: 42 Hom.: 5 AF XY: 0.441 AC XY: 15 AN XY: 34

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.454 AC: 69041 AN: 152074 Hom.: 15931 Cov.: 33 AF XY: 0.459 AC XY: 34117 AN XY: 74344

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.514

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.451

Alfa AF: 0.474 Hom.: 9771

Bravo AF: 0.434

Asia WGS AF: 0.558 AC: 1937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.70

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: rs12901499; hg19: chr15-67370445;