15-67174541-T-G

Variant names:

• chr15-67174541-T-G
• rs2278545
• NM_005902.4:c.658+3937T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005902.4(SMAD3):​c.658+3937T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,234 control chromosomes in the GnomAD database, including 58,376 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 0.87 (58280 hom., cov: 30)
  • Exomes 𝑓: 0.90 (96 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.9 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.658+3937T>G		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.658+3937T>G		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.526+3937T>G		intron	N/A	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.658+3937T>G		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.526+3937T>G		intron	N/A	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.343+3937T>G		intron	N/A	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.875 AC: 132880 AN: 151876 Hom.: 58233 Cov.: 30

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.814

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.884

GnomAD4 exome AF: 0.896 AC: 215 AN: 240 Hom.: 96 Cov.: 0 AF XY: 0.897 AC XY: 156 AN XY: 174

African (AFR) AF: 1.00 AC: 14 AN: 14

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 1.00 AC: 6 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.722 AC: 13 AN: 18

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.900 AC: 162 AN: 180

Other (OTH) AF: 0.875 AC: 14 AN: 16

GnomAD4 genome AF: 0.875 AC: 132983 AN: 151994 Hom.: 58280 Cov.: 30 AF XY: 0.873 AC XY: 64822 AN XY: 74250

African (AFR) AF: 0.860 AC: 35632 AN: 41440

American (AMR) AF: 0.913 AC: 13952 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3038 AN: 3472

East Asian (EAS) AF: 0.763 AC: 3923 AN: 5144

South Asian (SAS) AF: 0.813 AC: 3906 AN: 4802

European-Finnish (FIN) AF: 0.864 AC: 9125 AN: 10562

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.890 AC: 60471 AN: 67974

Other (OTH) AF: 0.885 AC: 1866 AN: 2108

Alfa AF: 0.885 Hom.: 41514

Bravo AF: 0.882

Asia WGS AF: 0.783 AC: 2724 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.9
DANN	Benign	0.58
PhyloP100		1.3
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: rs2278545; hg19: chr15-67466879;