15-67194437-T-C

Position:

• chr15-67194437-T-C

Variant summary

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

The NM_005902.4(SMAD3):​c.*3901T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 232,908 control chromosomes in the GnomAD database, including 10,311 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 0.31 (7441 hom., cov: 32)
  • Exomes 𝑓: 0.26 (2870 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.*3901T>C		3_prime_UTR_variant	9/9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.*3901T>C		3_prime_UTR_variant	9/9	1	NM_005902.4	ENSP00000332973	P1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46502 AN: 151854 Hom.: 7441 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.260 AC: 21079 AN: 80936 Hom.: 2870 Cov.: 0 AF XY: 0.262 AC XY: 9749 AN XY: 37194

Gnomad4 AFR exome AF: 0.400

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.241

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.306 AC: 46527 AN: 151972 Hom.: 7441 Cov.: 32 AF XY: 0.308 AC XY: 22865 AN XY: 74284

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.286

Alfa AF: 0.246 Hom.: 4684

Bravo AF: 0.313

Asia WGS AF: 0.326 AC: 1132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.75

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: rs3743343; hg19: chr15-67486775;