rs7173811

Variant names:

• chr15-67186713-T-C
• rs7173811
• NM_005902.4:c.1010-652T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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 -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 rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1010-652T>C		intron_variant	Intron 7 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1010-652T>C		intron_variant	Intron 7 of 8	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

African (AFR) AF: 0.374 AC: 190 AN: 508

American (AMR) AF: 0.280 AC: 713 AN: 2544

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 258 AN: 662

East Asian (EAS) AF: 0.133 AC: 175 AN: 1316

South Asian (SAS) AF: 0.301 AC: 1399 AN: 4650

European-Finnish (FIN) AF: 0.497 AC: 760 AN: 1530

Middle Eastern (MID) AF: 0.433 AC: 58 AN: 134

European-Non Finnish (NFE) AF: 0.489 AC: 9920 AN: 20266

Other (OTH) AF: 0.472 AC: 908 AN: 1922

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

African (AFR) AF: 0.417 AC: 17296 AN: 41502

American (AMR) AF: 0.359 AC: 5489 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1459 AN: 3470

East Asian (EAS) AF: 0.193 AC: 1002 AN: 5190

South Asian (SAS) AF: 0.331 AC: 1597 AN: 4822

European-Finnish (FIN) AF: 0.513 AC: 5436 AN: 10594

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35422 AN: 68002

Other (OTH) AF: 0.444 AC: 937 AN: 2112

Alfa AF: 0.497 Hom.: 23759

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
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7173811; hg19: chr15-67479051;