NM_005902.4:c.206+11691A>G

Variant names:

• chr15-67078051-A-G
• rs12901071
• NM_005902.4:c.206+11691A>G

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+11691A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,254 control chromosomes in the GnomAD database, including 5,935 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 (5932 hom., cov: 33)
  • Exomes 𝑓: 0.26 (3 hom.)
• Consequence: SMAD3 NM_005902.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• Publications: 25 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=-0.47).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.388 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+11691A>G		intron	N/A	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.206+11691A>G		intron	N/A	NP_001393940.1	H3BQ00
	SMAD3	NM_001407012.1		c.206+11691A>G		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+11691A>G		intron	N/A	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000560424.2	TSL:3	c.206+11691A>G		intron	N/A	ENSP00000455540.2	H3BQ00
	SMAD3	ENST00000714110.1		c.206+11691A>G		intron	N/A	ENSP00000519402.1	A0AAQ5BHK2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38096 AN: 152098 Hom.: 5938 Cov.: 33

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.263 AC: 10 AN: 38 Hom.: 3 Cov.: 0 AF XY: 0.179 AC XY: 5 AN XY: 28

African (AFR) AF: 0.00 AC: 0 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: 3 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.250 AC: 7 AN: 28

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.250 AC: 38077 AN: 152216 Hom.: 5932 Cov.: 33 AF XY: 0.254 AC XY: 18887 AN XY: 74398

African (AFR) AF: 0.0691 AC: 2873 AN: 41576

American (AMR) AF: 0.187 AC: 2863 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1068 AN: 5180

South Asian (SAS) AF: 0.403 AC: 1941 AN: 4818

European-Finnish (FIN) AF: 0.375 AC: 3961 AN: 10576

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.342 AC: 23228 AN: 67982

Other (OTH) AF: 0.262 AC: 553 AN: 2112

Alfa AF: 0.297 Hom.: 9503

Bravo AF: 0.221

Asia WGS AF: 0.278 AC: 968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		-0.20
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: rs12901071; hg19: chr15-67370389;