15-67066127-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005902.4(SMAD3):c.-28C>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 0.00294 in 1,550,850 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (65 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (39 hom.)
• Consequence: SMAD3 NM_005902.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.134

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 15-67066127-C-T is Benign according to our data. Variant chr15-67066127-C-T is described in ClinVar as [Benign]. Clinvar id is 139214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.-28C>T		5_prime_UTR_variant	1/9	ENST00000327367.9
SMAD3	NM_001407011.1	c.-28C>T		5_prime_UTR_variant	1/10
SMAD3	NM_001407012.1	c.-28C>T		5_prime_UTR_variant	1/8
SMAD3	NM_001407013.1	c.-28C>T		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.-28C>T		5_prime_UTR_variant	1/9	1	NM_005902.4	P1
SMAD3	ENST00000560424.2	c.-28C>T		5_prime_UTR_variant	1/10	3
SMAD3	ENST00000559460.6	c.-110+2183C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 151404 Hom.: 65 Cov.: 31

Gnomad AFR AF: 0.0533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000266

Gnomad OTH AF: 0.00481

GnomAD3 exomes AF: 0.00334 AC: 535 AN: 160088 Hom.: 7 AF XY: 0.00279 AC XY: 241 AN XY: 86316

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000423

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000323

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00161 AC: 2258 AN: 1399336 Hom.: 39 Cov.: 29 AF XY: 0.00148 AC XY: 1022 AN XY: 691456

Gnomad4 AFR exome AF: 0.0547

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.0152 AC: 2308 AN: 151514 Hom.: 65 Cov.: 31 AF XY: 0.0144 AC XY: 1067 AN XY: 74062

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.00498

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000266

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00829 Hom.: 3

Bravo AF: 0.0174

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2013

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

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	-0.34
Cadd	Benign	16
Dann	Uncertain	0.97

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: rs144374592; hg19: chr15-67358465;