rs36221701

Positions:

• chr15-67064151-T-C
• chr15-67064151-T-G

Variant summary

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

The NR_135686.1(SMAD3-DT):​n.32A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,356 control chromosomes in the GnomAD database, including 1,721 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 0.14 (1721 hom., cov: 33)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: SMAD3-DT NR_135686.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622

Genes affected

SMAD3-DT (HGNC:56759): (SMAD3 divergent transcript)

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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3-DT	NR_135686.1	n.32A>G		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000559460.6	c.-110+207T>C		intron_variant		4		ENSP00000453082
SMAD3-DT	ENST00000636067.1	n.1118A>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20696 AN: 152186 Hom.: 1703 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0946

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.154 AC: 8 AN: 52 Hom.: 0 Cov.: 0 AF XY: 0.107 AC XY: 3 AN XY: 28

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.136 AC: 20767 AN: 152304 Hom.: 1721 Cov.: 33 AF XY: 0.137 AC XY: 10171 AN XY: 74478

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0945

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.0884

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.132

Alfa AF: 0.0407 Hom.: 34

Bravo AF: 0.137

Asia WGS AF: 0.196 AC: 679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs36221701; hg19: chr15-67356489;