15-67191959-C-T

Variant names:

• chr15-67191959-C-T
• rs2278670
• NM_005902.4:c.*1423C>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.*1423C>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 0.223 in 228,792 control chromosomes in the GnomAD database, including 6,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3822 hom., cov: 32)
  • Exomes 𝑓: 0.26 (3161 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.848
• Publications: 16 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=-0.86).
• BP6: Variant 15-67191959-C-T is Benign according to our data. Variant chr15-67191959-C-T is described in ClinVar as Benign. ClinVar VariationId is 316902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.*1423C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.*1423C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30632 AN: 152034 Hom.: 3821 Cov.: 32

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.265 AC: 20294 AN: 76642 Hom.: 3161 Cov.: 0 AF XY: 0.264 AC XY: 9370 AN XY: 35450

African (AFR) AF: 0.0743 AC: 271 AN: 3646

American (AMR) AF: 0.312 AC: 736 AN: 2356

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1603 AN: 4780

East Asian (EAS) AF: 0.477 AC: 5179 AN: 10862

South Asian (SAS) AF: 0.300 AC: 196 AN: 654

European-Finnish (FIN) AF: 0.146 AC: 69 AN: 472

Middle Eastern (MID) AF: 0.287 AC: 131 AN: 456

European-Non Finnish (NFE) AF: 0.226 AC: 10628 AN: 47012

Other (OTH) AF: 0.231 AC: 1481 AN: 6404

GnomAD4 genome AF: 0.201 AC: 30652 AN: 152150 Hom.: 3822 Cov.: 32 AF XY: 0.206 AC XY: 15350 AN XY: 74368

African (AFR) AF: 0.0739 AC: 3066 AN: 41510

American (AMR) AF: 0.317 AC: 4841 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2399 AN: 5180

South Asian (SAS) AF: 0.286 AC: 1379 AN: 4816

European-Finnish (FIN) AF: 0.181 AC: 1915 AN: 10570

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

European-Non Finnish (NFE) AF: 0.222 AC: 15122 AN: 67994

Other (OTH) AF: 0.239 AC: 505 AN: 2114

Alfa AF: 0.184 Hom.: 470

Bravo AF: 0.207

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 13, 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	-0.86
CADD	Benign	0.55
DANN	Benign	0.41
PhyloP100		-0.85
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: rs2278670; hg19: chr15-67484297;