rs2289791

Positions:

• chr15-67184614-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005902.4(SMAD3):​c.872-113G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,325,804 control chromosomes in the GnomAD database, including 46,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4561 hom., cov: 32)
  • Exomes 𝑓: 0.26 (42010 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.62

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-67184614-G-T is Benign according to our data. Variant chr15-67184614-G-T is described in ClinVar as [Benign]. Clinvar id is 673139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.872-113G>T		intron_variant		ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.872-113G>T		intron_variant		1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35296 AN: 152092 Hom.: 4556 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.260 AC: 305182 AN: 1173594 Hom.: 42010 AF XY: 0.260 AC XY: 154957 AN XY: 595358

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.371

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.497

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.232 AC: 35344 AN: 152210 Hom.: 4561 Cov.: 32 AF XY: 0.237 AC XY: 17623 AN XY: 74430

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.258

Alfa AF: 0.235 Hom.: 557

Bravo AF: 0.237

Asia WGS AF: 0.348 AC: 1209 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2289791; hg19: chr15-67476952;