15-67121899-A-T

Variant names:

• chr15-67121899-A-T
• rs4776892
• NM_005902.4:c.207-42996A>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.207-42996A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,148 control chromosomes in the GnomAD database, including 5,311 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 0.25 (5311 hom., cov: 33)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 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.207-42996A>T		intron	N/A	NP_005893.1
	SMAD3	NM_001407011.1		c.207-42996A>T		intron	N/A	NP_001393940.1
	SMAD3	NM_001407012.1		c.207-42996A>T		intron	N/A	NP_001393941.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.207-42996A>T		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000560424.2	TSL:3	c.207-42996A>T		intron	N/A	ENSP00000455540.2
	SMAD3	ENST00000714110.1		c.207-42996A>T		intron	N/A	ENSP00000519402.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37752 AN: 152030 Hom.: 5296 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.237

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

GnomAD4 genome AF: 0.249 AC: 37815 AN: 152148 Hom.: 5311 Cov.: 33 AF XY: 0.251 AC XY: 18658 AN XY: 74382

African (AFR) AF: 0.332 AC: 13780 AN: 41492

American (AMR) AF: 0.301 AC: 4606 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 852 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2590 AN: 5170

South Asian (SAS) AF: 0.350 AC: 1688 AN: 4816

European-Finnish (FIN) AF: 0.145 AC: 1532 AN: 10596

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12089 AN: 67988

Other (OTH) AF: 0.236 AC: 498 AN: 2112

Alfa AF: 0.0834 Hom.: 101

Bravo AF: 0.265

Asia WGS AF: 0.389 AC: 1352 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	0.076
DANN	Benign	0.74
PhyloP100		-1.4
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: rs4776892; hg19: chr15-67414237;