rs2289791

Variant names:

• chr15-67184614-G-T
• rs2289791
• NM_005902.4:c.872-113G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.872-113G>T		intron_variant	Intron 6 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.872-113G>T		intron_variant	Intron 6 of 8	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

African (AFR) AF: 0.128 AC: 3579 AN: 27982

American (AMR) AF: 0.371 AC: 15898 AN: 42882

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8169 AN: 24188

East Asian (EAS) AF: 0.497 AC: 19002 AN: 38208

South Asian (SAS) AF: 0.282 AC: 22370 AN: 79264

European-Finnish (FIN) AF: 0.211 AC: 9230 AN: 43814

Middle Eastern (MID) AF: 0.315 AC: 1154 AN: 3664

European-Non Finnish (NFE) AF: 0.246 AC: 212345 AN: 862576

Other (OTH) AF: 0.263 AC: 13435 AN: 51016

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

African (AFR) AF: 0.134 AC: 5581 AN: 41544

American (AMR) AF: 0.331 AC: 5060 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1177 AN: 3472

East Asian (EAS) AF: 0.477 AC: 2461 AN: 5160

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4824

European-Finnish (FIN) AF: 0.223 AC: 2363 AN: 10606

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16532 AN: 67994

Other (OTH) AF: 0.258 AC: 544 AN: 2110

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

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.90
PhyloP100		-1.6
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289791; hg19: chr15-67476952;