15-67093131-C-G

Variant names:

• chr15-67093131-C-G
• rs1465841
• NM_005902.4:c.206+26771C>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.206+26771C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,048 control chromosomes in the GnomAD database, including 24,185 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 0.56 (24185 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• Publications: 7 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.729 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.206+26771C>G		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.206+26771C>G		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001407012.1		c.206+26771C>G		intron	N/A	NP_001393941.1	A0AAQ5BHI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.206+26771C>G		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000560424.2	TSL:3	c.206+26771C>G		intron	N/A	ENSP00000455540.2	H3BQ00
	SMAD3	ENST00000714110.1		c.206+26771C>G		intron	N/A	ENSP00000519402.1	A0AAQ5BHK2

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84990 AN: 151930 Hom.: 24178 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.559 AC: 85029 AN: 152048 Hom.: 24185 Cov.: 33 AF XY: 0.565 AC XY: 41983 AN XY: 74328

African (AFR) AF: 0.468 AC: 19370 AN: 41406

American (AMR) AF: 0.630 AC: 9620 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3472

East Asian (EAS) AF: 0.692 AC: 3589 AN: 5186

South Asian (SAS) AF: 0.750 AC: 3619 AN: 4828

European-Finnish (FIN) AF: 0.581 AC: 6147 AN: 10578

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38678 AN: 67978

Other (OTH) AF: 0.580 AC: 1227 AN: 2116

Alfa AF: 0.438 Hom.: 1206

Bravo AF: 0.554

Asia WGS AF: 0.657 AC: 2284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		-0.011
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs1465841; hg19: chr15-67385469;