rs12595334

Positions:

• chr15-67192818-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.*2282C>T		3_prime_UTR_variant	9/9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.*2282C>T		3_prime_UTR_variant	9/9	1	NM_005902.4	ENSP00000332973	P1

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

Gnomad4 AFR exome AF: 0.0783

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.337

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.236

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

Gnomad4 AFR AF: 0.0739

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.239

Alfa AF: 0.234 Hom.: 4496

Bravo AF: 0.207

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 24583347) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Aneurysm-osteoarthritis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs12595334; hg19: chr15-67485156;