rs8031440

Positions:

• chr15-67191641-G-A
• chr15-67191641-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005902.4(SMAD3):​c.*1105G>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 0.224 in 232,796 control chromosomes in the GnomAD database, including 7,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3819 hom., cov: 32)
  • Exomes 𝑓: 0.27 (3355 hom.)
• Consequence: SMAD3 NM_005902.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.93

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-67191641-G-A is Benign according to our data. Variant chr15-67191641-G-A is described in ClinVar as [Benign]. Clinvar id is 316892.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.*1105G>A		3_prime_UTR_variant	9/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.*1105G>A		3_prime_UTR_variant	9/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30634 AN: 152042 Hom.: 3818 Cov.: 32

Gnomad AFR AF: 0.0741

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.463

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: 0.267 AC: 21534 AN: 80636 Hom.: 3355 Cov.: 0 AF XY: 0.266 AC XY: 9878 AN XY: 37074

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.337

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.201 AC: 30654 AN: 152160 Hom.: 3819 Cov.: 32 AF XY: 0.206 AC XY: 15355 AN XY: 74392

Gnomad4 AFR AF: 0.0741

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.222

Gnomad4 OTH AF: 0.239

Alfa AF: 0.229 Hom.: 4202

Bravo AF: 0.207

Asia WGS AF: 0.336 AC: 1168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 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 12, 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	13
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs8031440; hg19: chr15-67483979;