rs12901499

Variant names:

• chr15-67078107-G-A
• rs12901499
• NM_005902.4:c.206+11747G>A

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+11747G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,116 control chromosomes in the GnomAD database, including 15,936 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 0.45 (15931 hom., cov: 33)
  • Exomes 𝑓: 0.45 (5 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• Publications: 38 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=-0.69).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.206+11747G>A		intron	N/A	NP_005893.1
	SMAD3	NM_001407011.1		c.206+11747G>A		intron	N/A	NP_001393940.1
	SMAD3	NM_001407012.1		c.206+11747G>A		intron	N/A	NP_001393941.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.206+11747G>A		intron	N/A	ENSP00000332973.4
	SMAD3	ENST00000560424.2	TSL:3	c.206+11747G>A		intron	N/A	ENSP00000455540.2
	SMAD3	ENST00000714110.1		c.206+11747G>A		intron	N/A	ENSP00000519402.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68978 AN: 151956 Hom.: 15909 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.452 AC: 19 AN: 42 Hom.: 5 AF XY: 0.441 AC XY: 15 AN XY: 34

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 16 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136336), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.454 AC: 69041 AN: 152074 Hom.: 15931 Cov.: 33 AF XY: 0.459 AC XY: 34117 AN XY: 74344

African (AFR) AF: 0.431 AC: 17863 AN: 41434

American (AMR) AF: 0.358 AC: 5476 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1732 AN: 3470

East Asian (EAS) AF: 0.514 AC: 2656 AN: 5172

South Asian (SAS) AF: 0.650 AC: 3136 AN: 4822

European-Finnish (FIN) AF: 0.485 AC: 5130 AN: 10576

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31659 AN: 67984

Other (OTH) AF: 0.451 AC: 954 AN: 2114

Alfa AF: 0.473 Hom.: 10579

Bravo AF: 0.434

Asia WGS AF: 0.558 AC: 1937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.70
PhyloP100		1.2
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: rs12901499; hg19: chr15-67370445;