rs187952791

Variant names:

• chr15-67066220-G-A
• rs187952791
• NM_005902.4:c.66G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005902.4(SMAD3):​c.66G>A​(p.Glu22Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,613,362 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: SMAD3 NM_005902.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.47
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-67066220-G-A is Benign according to our data. Variant chr15-67066220-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000571 (87/152252) while in subpopulation EAS AF = 0.0169 (87/5158). AF 95% confidence interval is 0.014. There are 3 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 87 Unknown,AD gene.

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.66G>A	p.Glu22Glu	synonymous	Exon 1 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.66G>A	p.Glu22Glu	synonymous	Exon 1 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001407012.1		c.66G>A	p.Glu22Glu	synonymous	Exon 1 of 8	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.66G>A	p.Glu22Glu	synonymous	Exon 1 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000560424.2	TSL:3	c.66G>A	p.Glu22Glu	synonymous	Exon 1 of 10	ENSP00000455540.2	H3BQ00
	SMAD3	ENST00000714110.1		c.66G>A	p.Glu22Glu	synonymous	Exon 1 of 9	ENSP00000519402.1	A0AAQ5BHK2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152134 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00138 AC: 344 AN: 248530 AF XY: 0.00128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000383 AC: 560 AN: 1461110 Hom.: 4 Cov.: 33 AF XY: 0.000378 AC XY: 275 AN XY: 726808

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0128 AC: 507 AN: 39676

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111770

Other (OTH) AF: 0.000414 AC: 25 AN: 60344

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152252 Hom.: 3 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0169 AC: 87 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000642

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial thoracic aortic aneurysm and aortic dissection (5)
-	-	3	not specified (3)
-	-	2	Aneurysm-osteoarthritis syndrome (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.96
PhyloP100		2.5
Mutation Taster		=88/12	polymorphism

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: rs187952791; hg19: chr15-67358558; COSMIC: COSV59280962; COSMIC: COSV59280962;