NM_005902.4:c.*3901T>C

Variant names:

• chr15-67194437-T-C
• rs3743343
• NM_005902.4:c.*3901T>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.*3901T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 232,908 control chromosomes in the GnomAD database, including 10,311 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 0.31 (7441 hom., cov: 32)
  • Exomes 𝑓: 0.26 (2870 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 25 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 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.*3901T>C		3_prime_UTR	Exon 9 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.*3901T>C		3_prime_UTR	Exon 10 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.*3901T>C		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.*3901T>C		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000558739.2	TSL:3	c.*3901T>C		3_prime_UTR	Exon 9 of 9	ENSP00000453684.2	P84022-3
	SMAD3	ENST00000559460.6	TSL:4	c.*3901T>C		3_prime_UTR	Exon 9 of 9	ENSP00000453082.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46502 AN: 151854 Hom.: 7441 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.260 AC: 21079 AN: 80936 Hom.: 2870 Cov.: 0 AF XY: 0.262 AC XY: 9749 AN XY: 37194

African (AFR) AF: 0.400 AC: 1553 AN: 3880

American (AMR) AF: 0.340 AC: 849 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 1134 AN: 5114

East Asian (EAS) AF: 0.301 AC: 3466 AN: 11524

South Asian (SAS) AF: 0.405 AC: 284 AN: 702

European-Finnish (FIN) AF: 0.241 AC: 14 AN: 58

Middle Eastern (MID) AF: 0.233 AC: 114 AN: 490

European-Non Finnish (NFE) AF: 0.238 AC: 11883 AN: 49918

Other (OTH) AF: 0.264 AC: 1782 AN: 6754

GnomAD4 genome AF: 0.306 AC: 46527 AN: 151972 Hom.: 7441 Cov.: 32 AF XY: 0.308 AC XY: 22865 AN XY: 74284

African (AFR) AF: 0.401 AC: 16598 AN: 41424

American (AMR) AF: 0.314 AC: 4803 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1572 AN: 5170

South Asian (SAS) AF: 0.376 AC: 1816 AN: 4824

European-Finnish (FIN) AF: 0.293 AC: 3089 AN: 10536

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16983 AN: 67952

Other (OTH) AF: 0.286 AC: 602 AN: 2106

Alfa AF: 0.249 Hom.: 5760

Bravo AF: 0.313

Asia WGS AF: 0.326 AC: 1132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-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: rs3743343; hg19: chr15-67486775;