rs35874463

Variant names:

• chr15-67165360-A-G
• rs35874463
• NM_005902.4:c.508A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005902.4(SMAD3):​c.508A>G​(p.Ile170Val) variant causes a missense change. The variant allele was found at a frequency of 0.0491 in 1,614,100 control chromosomes in the GnomAD database, including 2,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I170I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (117 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2140 hom.)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 4.95
• Publications: 47 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00407815).
• BP6: Variant 15-67165360-A-G is Benign according to our data. Variant chr15-67165360-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 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.508A>G	p.Ile170Val	missense	Exon 3 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.508A>G	p.Ile170Val	missense	Exon 3 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.376A>G	p.Ile126Val	missense	Exon 3 of 9	NP_001138575.1	P84022-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.508A>G	p.Ile170Val	missense	Exon 3 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000439724.7	TSL:1	c.376A>G	p.Ile126Val	missense	Exon 3 of 9	ENSP00000401133.3	P84022-2
	SMAD3	ENST00000540846.6	TSL:1	c.193A>G	p.Ile65Val	missense	Exon 3 of 9	ENSP00000437757.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5203 AN: 152160 Hom.: 117 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0506

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0396 AC: 9960 AN: 251386 AF XY: 0.0411

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0558

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0525

Gnomad OTH exome AF: 0.0415

GnomAD4 exome AF: 0.0506 AC: 74008 AN: 1461822 Hom.: 2140 Cov.: 34 AF XY: 0.0506 AC XY: 36798 AN XY: 727214

African (AFR) AF: 0.00908 AC: 304 AN: 33480

American (AMR) AF: 0.0214 AC: 959 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1442 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0436 AC: 3765 AN: 86256

European-Finnish (FIN) AF: 0.0430 AC: 2298 AN: 53406

Middle Eastern (MID) AF: 0.0527 AC: 304 AN: 5766

European-Non Finnish (NFE) AF: 0.0558 AC: 62004 AN: 1111962

Other (OTH) AF: 0.0484 AC: 2923 AN: 60394

GnomAD4 genome AF: 0.0341 AC: 5198 AN: 152278 Hom.: 117 Cov.: 33 AF XY: 0.0335 AC XY: 2492 AN XY: 74456

African (AFR) AF: 0.0102 AC: 422 AN: 41560

American (AMR) AF: 0.0234 AC: 358 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0405 AC: 195 AN: 4820

European-Finnish (FIN) AF: 0.0469 AC: 498 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0506 AC: 3439 AN: 68012

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0435 Hom.: 280

Bravo AF: 0.0319

TwinsUK AF: 0.0488 AC: 181

ALSPAC AF: 0.0573 AC: 221

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0547 AC: 470

ExAC AF: 0.0402 AC: 4883

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0541

EpiControl AF: 0.0528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	3	Aneurysm-osteoarthritis syndrome (3)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Loeys-Dietz syndrome (1)
-	-	1	Thoracic aortic aneurysm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0041	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.30
Sift	Benign	0.33	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.12
MPC		1.0
ClinPred		0.011	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.18
Mutation Taster		=94/6	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: rs35874463; hg19: chr15-67457698; COSMIC: COSV59281888; COSMIC: COSV59281888;