chr15-67184632-T-C

Variant names:

• chr15-67184632-T-C
• rs2289790
• NM_005902.4:c.872-95T>C

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.872-95T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,472,636 control chromosomes in the GnomAD database, including 49,607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4440 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45167 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99
• Publications: 11 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=-0.87).
• BP6: Variant 15-67184632-T-C is Benign according to our data. Variant chr15-67184632-T-C is described in ClinVar as Benign. ClinVar VariationId is 673140.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.872-95T>C		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.872-95T>C		intron_variant	Intron 6 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34846 AN: 152100 Hom.: 4435 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.254 AC: 335957 AN: 1320416 Hom.: 45167 AF XY: 0.255 AC XY: 169242 AN XY: 664028

African (AFR) AF: 0.126 AC: 3862 AN: 30762

American (AMR) AF: 0.367 AC: 16169 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8364 AN: 25276

East Asian (EAS) AF: 0.498 AC: 19416 AN: 38966

South Asian (SAS) AF: 0.277 AC: 23016 AN: 82946

European-Finnish (FIN) AF: 0.210 AC: 9992 AN: 47582

Middle Eastern (MID) AF: 0.315 AC: 1270 AN: 4036

European-Non Finnish (NFE) AF: 0.242 AC: 239416 AN: 991056

Other (OTH) AF: 0.259 AC: 14452 AN: 55770

GnomAD4 genome AF: 0.229 AC: 34894 AN: 152220 Hom.: 4440 Cov.: 32 AF XY: 0.234 AC XY: 17399 AN XY: 74424

African (AFR) AF: 0.133 AC: 5544 AN: 41552

American (AMR) AF: 0.328 AC: 5010 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1139 AN: 3468

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

South Asian (SAS) AF: 0.276 AC: 1332 AN: 4826

European-Finnish (FIN) AF: 0.222 AC: 2355 AN: 10592

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

European-Non Finnish (NFE) AF: 0.239 AC: 16237 AN: 68004

Other (OTH) AF: 0.255 AC: 539 AN: 2116

Alfa AF: 0.235 Hom.: 767

Bravo AF: 0.235

Asia WGS AF: 0.344 AC: 1198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.18
DANN	Benign	0.75
PhyloP100		-2.0
PromoterAI		0.011	Neutral
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: rs2289790; hg19: chr15-67476970;