15-67108152-C-T

Variant names:

• chr15-67108152-C-T
• rs2118612
• NM_005902.4:c.206+41792C>T

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+41792C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,080 control chromosomes in the GnomAD database, including 38,219 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 0.70 (38219 hom., cov: 31)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.41
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.792 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+41792C>T		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.206+41792C>T		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001407012.1		c.206+41792C>T		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+41792C>T		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000560424.2	TSL:3	c.206+41792C>T		intron	N/A	ENSP00000455540.2	H3BQ00
	SMAD3	ENST00000714110.1		c.206+41792C>T		intron	N/A	ENSP00000519402.1	A0AAQ5BHK2

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106370 AN: 151962 Hom.: 38211 Cov.: 31

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.699

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

GnomAD4 genome AF: 0.700 AC: 106416 AN: 152080 Hom.: 38219 Cov.: 31 AF XY: 0.695 AC XY: 51695 AN XY: 74372

African (AFR) AF: 0.572 AC: 23702 AN: 41450

American (AMR) AF: 0.623 AC: 9531 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2502 AN: 3470

East Asian (EAS) AF: 0.469 AC: 2420 AN: 5164

South Asian (SAS) AF: 0.644 AC: 3102 AN: 4820

European-Finnish (FIN) AF: 0.801 AC: 8485 AN: 10596

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.797 AC: 54212 AN: 67978

Other (OTH) AF: 0.701 AC: 1479 AN: 2110

Alfa AF: 0.762 Hom.: 183915

Bravo AF: 0.679

Asia WGS AF: 0.581 AC: 2020 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0020
DANN	Benign	0.77
PhyloP100		-3.4
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: rs2118612; hg19: chr15-67400490;