rs3743342

Variant names:

• chr15-67193329-C-T
• rs3743342
• NM_005902.4:c.*2793C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-67193329-C-T
• chr15-67193329-C-G

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.*2793C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 233,310 control chromosomes in the GnomAD database, including 7,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3851 hom., cov: 32)
  • Exomes 𝑓: 0.27 (3381 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.741
• Publications: 23 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown 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=-0.8).
• BP6: Variant 15-67193329-C-T is Benign according to our data. Variant chr15-67193329-C-T is described in ClinVar as Benign. ClinVar VariationId is 316947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.*2793C>T		3_prime_UTR	Exon 9 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.*2793C>T		3_prime_UTR	Exon 10 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.*2793C>T		3_prime_UTR	Exon 9 of 9	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.*2793C>T		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000558739.2	TSL:3	c.*2793C>T		3_prime_UTR	Exon 9 of 9	ENSP00000453684.2	P84022-3
	SMAD3	ENST00000559460.6	TSL:4	c.*2793C>T		3_prime_UTR	Exon 9 of 9	ENSP00000453082.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30968 AN: 152042 Hom.: 3849 Cov.: 32

Gnomad AFR AF: 0.0813

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.268 AC: 21769 AN: 81148 Hom.: 3381 Cov.: 0 AF XY: 0.268 AC XY: 9990 AN XY: 37328

African (AFR) AF: 0.0850 AC: 331 AN: 3894

American (AMR) AF: 0.315 AC: 787 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1727 AN: 5124

East Asian (EAS) AF: 0.481 AC: 5548 AN: 11544

South Asian (SAS) AF: 0.296 AC: 208 AN: 702

European-Finnish (FIN) AF: 0.134 AC: 11 AN: 82

Middle Eastern (MID) AF: 0.293 AC: 144 AN: 492

European-Non Finnish (NFE) AF: 0.228 AC: 11412 AN: 50036

Other (OTH) AF: 0.236 AC: 1601 AN: 6776

GnomAD4 genome AF: 0.204 AC: 30988 AN: 152162 Hom.: 3851 Cov.: 32 AF XY: 0.208 AC XY: 15496 AN XY: 74372

African (AFR) AF: 0.0812 AC: 3372 AN: 41542

American (AMR) AF: 0.317 AC: 4852 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3470

East Asian (EAS) AF: 0.463 AC: 2388 AN: 5158

South Asian (SAS) AF: 0.286 AC: 1380 AN: 4826

European-Finnish (FIN) AF: 0.182 AC: 1919 AN: 10570

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15146 AN: 67996

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.217 Hom.: 6136

Bravo AF: 0.210

Asia WGS AF: 0.336 AC: 1170 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aneurysm-osteoarthritis syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		0.74
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3743342;

hg19: chr15-67485667;