15-67066132-C-T

Variant names:

• chr15-67066132-C-T
• rs36221703
• NM_005902.4:c.-23C>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.-23C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,557,014 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (132 hom.)
• Consequence: SMAD3 NM_005902.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.27
• Publications: 3 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: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-67066132-C-T is Benign according to our data. Variant chr15-67066132-C-T is described in ClinVar as [Benign]. Clinvar id is 139215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.-23C>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1	c.-23C>T		5_prime_UTR_variant	Exon 1 of 10		NP_001393940.1
SMAD3	NM_001407012.1	c.-23C>T		5_prime_UTR_variant	Exon 1 of 8		NP_001393941.1
SMAD3	NM_001407013.1	c.-23C>T		5_prime_UTR_variant	Exon 1 of 8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.-23C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 545 AN: 151690 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.000380

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000516

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00856 AC: 1427 AN: 166720 AF XY: 0.00935

Gnomad AFR exome AF: 0.000792

Gnomad AMR exome AF: 0.000342

Gnomad ASJ exome AF: 0.000588

Gnomad EAS exome AF: 0.0628

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.000667

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00358 AC: 5032 AN: 1405214 Hom.: 132 Cov.: 29 AF XY: 0.00424 AC XY: 2948 AN XY: 694662

African (AFR) AF: 0.000375 AC: 12 AN: 32004

American (AMR) AF: 0.000348 AC: 13 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.000555 AC: 14 AN: 25222

East Asian (EAS) AF: 0.0644 AC: 2360 AN: 36638

South Asian (SAS) AF: 0.0225 AC: 1807 AN: 80360

European-Finnish (FIN) AF: 0.000909 AC: 44 AN: 48382

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4110

European-Non Finnish (NFE) AF: 0.000372 AC: 403 AN: 1083050

Other (OTH) AF: 0.00643 AC: 374 AN: 58130

GnomAD4 genome AF: 0.00362 AC: 549 AN: 151800 Hom.: 15 Cov.: 32 AF XY: 0.00462 AC XY: 343 AN XY: 74202

African (AFR) AF: 0.000579 AC: 24 AN: 41456

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.0645 AC: 330 AN: 5116

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4822

European-Finnish (FIN) AF: 0.000380 AC: 4 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000516 AC: 35 AN: 67808

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00328

Asia WGS AF: 0.0530 AC: 183 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Loeys-Dietz syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aneurysm-osteoarthritis syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.54
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		1.3
Mutation Taster		=299/1	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: rs36221703; hg19: chr15-67358470;