rs7173811

Positions:

• chr15-67186713-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.1010-652T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 185,730 control chromosomes in the GnomAD database, including 19,654 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 (16179 hom., cov: 33)
  • Exomes 𝑓: 0.43 (3475 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1010-652T>C		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1010-652T>C		intron_variant		1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69235 AN: 152080 Hom.: 16187 Cov.: 33

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.429 AC: 14381 AN: 33532 Hom.: 3475 Cov.: 0 AF XY: 0.417 AC XY: 7234 AN XY: 17332

Gnomad4 AFR exome AF: 0.374

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.301

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.489

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.455 AC: 69236 AN: 152198 Hom.: 16179 Cov.: 33 AF XY: 0.449 AC XY: 33404 AN XY: 74392

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.444

Alfa AF: 0.504 Hom.: 18441

Bravo AF: 0.442

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.4
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7173811; hg19: chr15-67479051;