rs8031627

Variant names:

• chr15-67191781-G-A
• rs8031627
• NM_005902.4:c.*1245G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-67191781-G-A
• chr15-67191781-G-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.*1245G>A 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 230,062 control chromosomes in the GnomAD database, including 7,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3813 hom., cov: 32)
  • Exomes 𝑓: 0.26 (3200 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.539
• Publications: 21 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=-0.73).
• BP6: Variant 15-67191781-G-A is Benign according to our data. Variant chr15-67191781-G-A is described in ClinVar as Benign. ClinVar VariationId is 316896.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 rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.*1245G>A		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.*1245G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30611 AN: 152062 Hom.: 3812 Cov.: 32

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.237

GnomAD4 exome AF: 0.265 AC: 20621 AN: 77882 Hom.: 3200 Cov.: 0 AF XY: 0.264 AC XY: 9479 AN XY: 35878

African (AFR) AF: 0.0788 AC: 294 AN: 3730

American (AMR) AF: 0.312 AC: 748 AN: 2396

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1648 AN: 4934

East Asian (EAS) AF: 0.474 AC: 5231 AN: 11034

South Asian (SAS) AF: 0.302 AC: 205 AN: 678

European-Finnish (FIN) AF: 0.116 AC: 13 AN: 112

Middle Eastern (MID) AF: 0.296 AC: 142 AN: 480

European-Non Finnish (NFE) AF: 0.226 AC: 10829 AN: 48022

Other (OTH) AF: 0.233 AC: 1511 AN: 6496

GnomAD4 genome AF: 0.201 AC: 30631 AN: 152180 Hom.: 3813 Cov.: 32 AF XY: 0.206 AC XY: 15339 AN XY: 74384

African (AFR) AF: 0.0737 AC: 3061 AN: 41540

American (AMR) AF: 0.316 AC: 4836 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1150 AN: 3470

East Asian (EAS) AF: 0.462 AC: 2393 AN: 5178

South Asian (SAS) AF: 0.286 AC: 1378 AN: 4820

European-Finnish (FIN) AF: 0.181 AC: 1918 AN: 10580

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.222 AC: 15117 AN: 67988

Other (OTH) AF: 0.238 AC: 503 AN: 2110

Alfa AF: 0.217 Hom.: 5462

Bravo AF: 0.207

Asia WGS AF: 0.335 AC: 1164 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 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	-0.73
CADD	Benign	12
DANN	Benign	0.74
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: rs8031627; hg19: chr15-67484119; COSMIC: COSV107381610; COSMIC: COSV107381610;