15-67135996-T-C

Variant names:

• chr15-67135996-T-C
• rs2118610
• NM_005902.4:c.207-28899T>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.207-28899T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,006 control chromosomes in the GnomAD database, including 27,900 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 0.60 (27900 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 23 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.207-28899T>C		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.207-28899T>C		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91256 AN: 151888 Hom.: 27871 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.897

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.631

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

GnomAD4 genome AF: 0.601 AC: 91332 AN: 152006 Hom.: 27900 Cov.: 32 AF XY: 0.611 AC XY: 45368 AN XY: 74294

African (AFR) AF: 0.583 AC: 24116 AN: 41396

American (AMR) AF: 0.695 AC: 10624 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2388 AN: 3470

East Asian (EAS) AF: 0.898 AC: 4655 AN: 5186

South Asian (SAS) AF: 0.794 AC: 3827 AN: 4820

European-Finnish (FIN) AF: 0.589 AC: 6226 AN: 10566

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.551 AC: 37482 AN: 67974

Other (OTH) AF: 0.635 AC: 1343 AN: 2114

Alfa AF: 0.575 Hom.: 78369

Bravo AF: 0.607

Asia WGS AF: 0.820 AC: 2853 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		-0.17
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: rs2118610; hg19: chr15-67428334;