rs12595334

Variant names:

• chr15-67192818-C-T
• rs12595334
• NM_005902.4:c.*2282C>T

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.*2282C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 233,046 control chromosomes in the GnomAD database, including 7,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3833 hom., cov: 32)
  • Exomes 𝑓: 0.27 (3350 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.535
• Publications: 22 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 (BayesDel_noAF=-0.79).
• BP6: Variant 15-67192818-C-T is Benign according to our data. Variant chr15-67192818-C-T is described in ClinVar as Benign. ClinVar VariationId is 316934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 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.*2282C>T		3_prime_UTR	Exon 9 of 9	NP_005893.1	P84022-1
	SMAD3	NM_001407011.1		c.*2282C>T		3_prime_UTR	Exon 10 of 10	NP_001393940.1	H3BQ00
	SMAD3	NM_001145103.2		c.*2282C>T		3_prime_UTR	Exon 9 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.*2282C>T		3_prime_UTR	Exon 9 of 9	ENSP00000332973.4	P84022-1
	SMAD3	ENST00000558739.2	TSL:3	c.*2282C>T		3_prime_UTR	Exon 9 of 9	ENSP00000453684.2	P84022-3
	SMAD3	ENST00000559460.6	TSL:4	c.*2282C>T		3_prime_UTR	Exon 9 of 9	ENSP00000453082.2	P84022-3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30667 AN: 152060 Hom.: 3832 Cov.: 32

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.267 AC: 21604 AN: 80868 Hom.: 3350 Cov.: 0 AF XY: 0.267 AC XY: 9920 AN XY: 37186

African (AFR) AF: 0.0783 AC: 304 AN: 3884

American (AMR) AF: 0.312 AC: 778 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1720 AN: 5106

East Asian (EAS) AF: 0.477 AC: 5490 AN: 11508

South Asian (SAS) AF: 0.296 AC: 207 AN: 700

European-Finnish (FIN) AF: 0.155 AC: 9 AN: 58

Middle Eastern (MID) AF: 0.292 AC: 143 AN: 490

European-Non Finnish (NFE) AF: 0.228 AC: 11362 AN: 49876

Other (OTH) AF: 0.236 AC: 1591 AN: 6752

GnomAD4 genome AF: 0.202 AC: 30686 AN: 152178 Hom.: 3833 Cov.: 32 AF XY: 0.207 AC XY: 15367 AN XY: 74400

African (AFR) AF: 0.0739 AC: 3066 AN: 41516

American (AMR) AF: 0.317 AC: 4838 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2393 AN: 5170

South Asian (SAS) AF: 0.286 AC: 1379 AN: 4826

European-Finnish (FIN) AF: 0.182 AC: 1923 AN: 10594

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15155 AN: 68010

Other (OTH) AF: 0.239 AC: 505 AN: 2110

Alfa AF: 0.228 Hom.: 5650

Bravo AF: 0.207

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Aneurysm-osteoarthritis syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.47
PhyloP100		0.54
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: rs12595334; hg19: chr15-67485156;