15-67081773-C-T

Variant names:

• chr15-67081773-C-T
• rs6494629
• NM_005902.4:c.206+15413C>T

Variant summary

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

The NM_001407011.1(SMAD3):​c.206+15413C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,734 control chromosomes in the GnomAD database, including 21,173 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 0.53 (21173 hom., cov: 29)
• Consequence: SMAD3 NM_001407011.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 16 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407011.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.206+15413C>T		intron	N/A	NP_005893.1
	SMAD3	NM_001407011.1		c.206+15413C>T		intron	N/A	NP_001393940.1
	SMAD3	NM_001407012.1		c.206+15413C>T		intron	N/A	NP_001393941.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.206+15413C>T		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000560424.2	TSL:3	c.206+15413C>T		intron	N/A	ENSP00000455540.2
	SMAD3	ENST00000714110.1		c.206+15413C>T		intron	N/A	ENSP00000519402.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79652 AN: 151616 Hom.: 21163 Cov.: 29

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.550

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.525 AC: 79687 AN: 151734 Hom.: 21173 Cov.: 29 AF XY: 0.529 AC XY: 39235 AN XY: 74112

African (AFR) AF: 0.466 AC: 19267 AN: 41368

American (AMR) AF: 0.574 AC: 8752 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1872 AN: 3464

East Asian (EAS) AF: 0.622 AC: 3196 AN: 5142

South Asian (SAS) AF: 0.722 AC: 3449 AN: 4780

European-Finnish (FIN) AF: 0.503 AC: 5297 AN: 10528

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36006 AN: 67880

Other (OTH) AF: 0.547 AC: 1154 AN: 2110

Alfa AF: 0.540 Hom.: 12485

Bravo AF: 0.525

Asia WGS AF: 0.598 AC: 2079 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	5.5
DANN	Benign	0.84
PhyloP100		0.12
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: rs6494629; hg19: chr15-67374111;