15-67071235-C-T

Variant names:

• chr15-67071235-C-T
• rs11632964
• NM_005902.4:c.206+4875C>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+4875C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,044 control chromosomes in the GnomAD database, including 11,176 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 0.37 (11176 hom., cov: 32)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 12 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.206+4875C>T		intron_variant	Intron 1 of 8	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.206+4875C>T		intron_variant	Intron 1 of 9		NP_001393940.1
SMAD3	NM_001407012.1	c.206+4875C>T		intron_variant	Intron 1 of 7		NP_001393941.1
SMAD3	NM_001407013.1	c.206+4875C>T		intron_variant	Intron 1 of 7		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.206+4875C>T		intron_variant	Intron 1 of 8	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55847 AN: 151924 Hom.: 11168 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.379

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

GnomAD4 genome AF: 0.368 AC: 55886 AN: 152044 Hom.: 11176 Cov.: 32 AF XY: 0.371 AC XY: 27576 AN XY: 74334

African (AFR) AF: 0.223 AC: 9235 AN: 41440

American (AMR) AF: 0.294 AC: 4498 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1549 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1677 AN: 5180

South Asian (SAS) AF: 0.552 AC: 2659 AN: 4820

European-Finnish (FIN) AF: 0.463 AC: 4899 AN: 10576

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30150 AN: 67952

Other (OTH) AF: 0.380 AC: 803 AN: 2114

Alfa AF: 0.347 Hom.: 2164

Bravo AF: 0.338

Asia WGS AF: 0.406 AC: 1409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.5
DANN	Benign	0.47
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: rs11632964; hg19: chr15-67363573;